liu.seSearch for publications in DiVA
Change search
Refine search result
1 - 42 of 42
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Rows per page
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sort
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
Select
The maximal number of hits you can export is 250. When you want to export more records please use the Create feeds function.
  • 1.
    Ansell, Anna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences.
    Kankainen, M.
    Institute of Biomedicine, Medical Biochemistry and Developmental Biology, Genome-Scale Biology, Research Program, University of Helsinki, Helsinki, Finland.
    Jönsson, Jan-Ingvar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Monni, O.
    Institute of Biomedicine, Medical Biochemistry and Developmental Biology, Genome-Scale Biology, Research Program, University of Helsinki, Helsinki, Finland.
    Roberg, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Otorhinolaryngology in Linköping.
    Johansson, Ann-Charlotte
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences.
    Molecular cross-talk between head and neck squamous cell carcinoma cells and cancer-associated fibroblasts2013Manuscript (preprint) (Other academic)
    Abstract [en]

    Cancer-associated fibroblasts (CAFs) are one of the main components of the tumor stroma and are known to increase tumor growth and stimulate  invasion and metastasis. Increasing evidence suggests that CAFs may also be an important determinant of the response to various treatments. In this study we aimed to characterize the molecular cross-talk between CAFs and head and neck squamous cell carcinoma (HNSCC) cells.

    HNSCC cell lines were co-cultured with their patient-matched CAFs for seven days, after which the gene expression of tumor cells was investigated by Affymetrix microarray. 58 protein coding genes were found to be differentially expressed (Q≤0.05) in tumor cells cocultured with CAFs when compared to tumor cells cultured alone. The top functions of these genes were cancer, cellular movement, and embryonic development as analyzed by Ingenuity Pathway Analysis. Nine genes were upregulated by ≥1.5-fold while the expression of 35 genes was found to be reduced by ≤ 0.67-fold. Several of the differentially expressed genes have been associated with epithelial-to-mesenchymal transition (EMT). The change in the expression of POSTN, GREM1, COL1A2, VIM, and MMP7 was verified by qPCR analysis. Moreover, the influence of CAFs on the proliferation, migration and cetuximab sensitivity of tumor cells was investigated, and was found to vary among the tumor cell-CAF pairs.

    In conclusion, we demonstrate that CAF-derived signals cause changes in the expression of multiple genes, several of which are associated with an EMT phenotype of tumor cells. Furthermore, CAFs modulate the proliferation, migration and cetuximab treatment response of tumor cells.

  • 2. Dannaeus, Karin
    et al.
    Bessonova, Marina
    Jönsson, Jan-Ingvar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology.
    Characterization of the mouse myeloid-associated differentiation marker (myadm) gene: Promoter analysis and protein localization2005In: Molecular Biology Reports, ISSN 0301-4851, E-ISSN 1573-4978, Vol. 32, no 3, p. 149-157Article in journal (Refereed)
    Abstract [en]

    Hematopoietic differentiation is a complex process involving many genes inducing functional changes and characteristics of different cell lineages. To understand this process, it is important to identify genes involved in lineage commitment and maturation of hematopoietic progenitor cells. Recently we isolated the novel gene MYADM which is strongly up-regulated as multipotent progenitor cells differentiate towards myeloid cells. Because it is not expressed in lymphocytes, understanding the transcriptional control of MYADM could further explain differences in gene expression between myeloid and lymphoid cells. To identify regulatory elements controlling its restricted expression, we have analyzed the 5′-flanking region of the MYADM gene. The proximal promoter was found to lack both TATA and CCAAT boxes, but contained several potential binding sites for both ubiquitous and myeloid-specific transcription factors. Maximal promoter activity was contained within 800∈bp from the tentative transcription initiation site, which was reduced as portions of the 5′-end were deleted, and completely abolished when the transcription initiation site was deleted. This promoter sequence had higher activity in myeloid cells compared to B cells, and activity was enhanced during myeloid differentiation, suggesting that we have identified the MYADM core promoter. Computer predictions had suggested MYADM to encode a protein with multiple transmembrane domains. By immunofluorescence and confocal microscopy we demonstrate that the protein is localized to the nuclear envelope and to intracytoplasmic membranes, indicating that MYADM constitutes an integral membrane protein. © Springer 2005.

  • 3. Ekoff, Maria
    et al.
    Kaufmann, Thomas
    Engström, Maria
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology.
    Motoyama, Noboru
    Villunger, Andreas
    Jönsson, Jan-Ingvar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology.
    Strasser, Andreas
    Nilsson, Gunnar
    The BH3-only protein Puma plays an essential role in cytokine deprivation-induced apoptosis of mast cells2007In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 110, no 9, p. 3209-3217Article in journal (Refereed)
    Abstract [en]

    Mast cells play critical roles in the regulation of inflammation. One characteristic feature of mast cells is their relatively long lifespan in vivo. Members of the Bcl-2 protein family are regulators of cell survival and apoptosis, where the BH3-only proteins are critical proapoptotic proteins. In this study we investigated the role of the BH3-only proteins Noxa, Bad, Bim, Bmf, Bid, and Puma in apoptosis of mucosal-like mast cells (MLMCs) and connective tissue-like mast cells (CTLMCs). We demonstrate that Puma is critical for the induction of mast-cell death following cytokine deprivation and treatment with the DNA-damaging agent etoposide in MLMCs and CTLMCs. Using p53-/- mast cells, we found that cytokine deprivation-induced apoptosis, in contrast to that elicited by etoposide, is p53-independent. Interestingly, mast cells deficient in FOXO3a, previously proposed as a transcription factor for Puma induction in response to growth factor deprivation, were markedly resistant to cytokine withdrawal compared with wildtype cells. Moreover, overexpression of phosphorylation-deficient, constitutively active FOXO3a caused an up-regulation of Puma. In conclusion, our data demonstrate a pivotal role for Puma in the regulation of cytokine deprivation-induced mast-cell apoptosis and suggest a plausible role for Puma in the regulation of mast cell numbers in vivo. © 2007 by The American Society of Hematology.

  • 4.
    Eliasson, Pernilla
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology.
    Andersson, Patiyan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology.
    Willander, Kerstin
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology.
    Linderholm, Mats
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Haematology UHL.
    Söderkvist, Peter
    Linköping University, Department of Biomedicine and Surgery, Division of cell biology. Linköping University, Faculty of Health Sciences.
    Jönsson, Jan-Ingvar
    Linköping University, Department of Biomedicine and Surgery, Division of cell biology. Linköping University, Faculty of Health Sciences.
    Letter: Absence of hot spot mutations of the PIK3CA gene in acute myeloid leukaemia2006In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 77, no 1, p. 86-87Article in journal (Other academic)
    Abstract [en]

    [No abstract available]

  • 5.
    Eliasson, Pernilla
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Jönsson, Jan-Ingvar
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology . Linköping University, Faculty of Health Sciences.
    The Hematopoietic Stem Cell Niche: Low in Oxygen but a Nice Place to be2010In: Journal of Cellular Physiology, ISSN 0021-9541, E-ISSN 1097-4652, Vol. 222, no 1, p. 17-22Article, review/survey (Refereed)
    Abstract [en]

    The enormous regenerative capacity of the blood system to sustain functionally mature cells are generated from highly proliferative, short-lived progenitors, which in turn arise from a rare population of pluripotent and self-renewing hematopoietic stem cells (HSC). In the bone marrow, these stem cells are kept in a low proliferative, relatively quiescent state in close proximity to stromal cells and osteoblasts, forming specialized niches. The interaction in particular to bone is crucial to prevent exhaustion of HSCs from uncontrolled cell-cycle entry and to excessive proliferation. In addition, the niche and its components protect stem cells from stress, such as accumulation of reactive oxygen species and DNA damage. One of the key issues is to identify conditions to increase the number of HSCs, either in vivo or during ex vivo growth cultures. This task has been very difficult to resolve and most attempts have been unsuccessful. However, the mechanistic insights to HSC self-renewal and preservation are gradually increasing and there is now hope that future research will enable scientists and clinicians to modulate the process. In this review, we will focus on the molecular mechanisms of self-renewal and HSC maintenance in the light of novel findings that HSCs reside at the lowest end of an oxygen gradient. Hypoxia appears to regulate hematopoiesis in the bone marrow by maintaining important HSC functions, such as cell cycle control, survival, metabolism, and protection against oxidative stress. To improve the therapeutic expansion of HSCs we need to learn more about the molecular mechanisms of hypoxia-mediated regulation.

  • 6.
    Eliasson, Pernilla
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Karlsson, Richard
    Lund University.
    Jönsson, Jan-Ingvar
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Hypoxia Expands Primitive Hematopoietic Progenitor Cells from Mouse Bone Marrow During In Vitro Culture and Preserves the Colony-Forming Ability2006In: Journal of Stem Cells, ISSN 1556-8539, Vol. 1, no 4, p. 247-257Article in journal (Refereed)
    Abstract [en]

    Self-renewal is a prerequisite for the maintenance of hematopoietic stem cells (HSCs) in the bone marrow throughout adult life. Cytokines are mainly providing pro-survival signals of HSC, whereas low oxygen levels (hypoxia) were recently shown to influence self-renewal. In contrast, the effects on other progenitor cell types is not clear. In the present work, we have analyzed whether hypoxia has any effects on mouse multipotent progenitors. When bone marrow-derived Lin-Sca1+c-kit+ (LSK) cells were kept in hypoxic cultures (1% O2 ) for 4 days together with cytokines, the numbers of colony forming high-proliferative progenitors (HPP-CFC) and precursors for cobble-stone forming cells (CAFC) were increased compared to normoxic conditions. A similar effect was seen with pre-CFCmulti from unfractionated bone marrow, whereas more committed progenitors (CFU-GM) were expanded better in normoxia compared to hypoxia. The observed increase in numbers of primitive colony-forming progenitor cells was associated with maintenance of the c-kit/Sca-1 phenotype and a preferential expansion of immature  blast-like appearing cells. The results suggest that a major function of hypoxia is to regulate differentiation by increased self-renewal. Furthermore, in cultures of limited cytokine supply, survival of the stem cell-like cell line FDCP-mix was increased during hypoxia. Thus, hypoxia allows for better survival and self-renewal of multipotent progenitors and HSCs from adult bone marrow. Such culture conditions may have beneficial clinical implications for ex vivo purposes and may improve the yields of stem cells and early progenitors.

  • 7.
    Eliasson, Pernilla
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Rehn, Matilda
    Lund Strategic Center for Stem Cell Biology and Cell Therapy, Lund University, SE-221 84 Lund, Sweden.
    Hammar, Petter
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Larsson, Peter
    Linköping University, Department of Medical and Health Sciences, Radiation Physics. Linköping University, Faculty of Health Sciences.
    Sirenko, Oksana
    FibroGen Inc., San Francisco, CA. USA.
    A Flippin, Lee
    FibroGen Inc., San Francisco, CA., USA.
    Cammenga, Jorg
    Lund Strategic Center for Stem Cell Biology and Cell Therapy, Lund University, SE-221 84 Lund, Sweden.
    Jönsson, Jan-Ingvar
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Hypoxia mediates low cell-cycle activity and increases the proportion of long-term reconstituting hematopoietic stem cells during in vitro culture2010In: Experimental Hematology, ISSN 0301-472X, E-ISSN 1873-2399, Vol. 38, no 4, p. 301-310Article in journal (Refereed)
    Abstract [en]

    Objective. Recent evidence suggests that hematopoietic stem cells (HSCs) in the bone marrow (BM) are located in areas where the environment is hypoxic. Although previous studies have demonstrated positive effects by hypoxia, its role in HSC maintenance has not been fully elucidated, neither has the molecular mechanisms been delineated. Here, we have investigated the consequence of in vitro incubation of HSCs in hypoxia prior to transplantation and analyzed the role of hypoxia-inducible factor (HIF)-1 alpha. Materials and Methods. HSC and progenitor populations isolated from mouse BM were cultured in 20% or 1% O-2, and analyzed for effects on cell cycle, expression of cyclin-dependent kinase inhibitors genes, and reconstituting ability to lethally irradiated mice. The involvement of HIF-1 alpha was studied using methods of protein stabilization and gene silencing. Results. When long-term FLT3(-)CD34(-)Lin(-)Sca-1(+)c-Kit(+) (LSK) cells were cultured in hypoxia, cell numbers were significantly reduced in comparison to normoxia. This was due to a decrease in proliferation and more cells accumulating in G(0). Moreover, the proportion of HSCs with long-term engraftment potential was increased. Whereas expression of the cyclin-dependent kinase inhibitor genes p21(cip1), p27(Kip1), and p57(Kip2) increased in LSK cells by hypoxia, only p21(cip1) was upregulated in FLT3(-)CD34(-)LSK cells. We could demonstrate that expression of p27(KiP1) and p57(Kip2) was dependent of HIF-1 alpha. Surprisingly, overexpression of constitutively active HIF-1 alpha or treatment with the HIF stabilizer agent FG-4497 led to a reduction in HSC reconstituting ability. Conclusions. Our results imply that hypoxia, in part via HIF-1 alpha, maintains HSCs by decreasing proliferation and favoring quiescence.

  • 8.
    Eliasson, Pernilla
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology . Linköping University, Faculty of Health Sciences.
    Widegren, Emma
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology . Linköping University, Faculty of Health Sciences.
    Jönsson, Jan-Ingvar
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology . Linköping University, Faculty of Health Sciences.
    Hypoxia rescues hematopoietic stem cells from oxidative stress-induced cell death and preserves the long-term repopulation abilityManuscript (preprint) (Other academic)
    Abstract [en]

    A balanced regulation of the ability of hematopoietic stem cells (HSCs) to undergo self-renewal and give rise to new blood cells is crucial for blood homeostasis. Recent studies utilizing genetically modified mice have demonstrated that reactive oxygen species (ROS) damage cellular functions and decrease the lifespan of long-term (LT) HSCs. These LT-HSCs are predominately located in a low-oxygen, or hypoxic, niche, essential for maintaining stem cell capacities. Here, we show that hypoxic culturing rescues HSCs from oxidative stress-induced cell death. Hypoxia inducible factor (HIF)-1 and its target gene pyruvate dehydrogenase kinase 1 (PDK1) were both crucial for survival and long term repopulating ability of HSCs, but less important for hypoxic resistance towards oxidative stress. Moreover, hypoxia increased the expression of Foxo3a, a transcription factor important in adaption to stress stimuli. In conclusion, hypoxia protects LT-HSCs from oxidative stress, possibly by multiple mechanisms, where Foxo3a is likely to play a central role.

  • 9.
    Engström, Linda
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Ruud, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Eskilsson, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Larsson, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Mackerlova, Ludmila
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Kugelberg, Unn
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Qian, Hong
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Vasilache, Ana Maria
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Larsson, Peter
    Linköping University, Department of Medical and Health Sciences, Radiation Physics. Linköping University, Faculty of Health Sciences.
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Jönsson, Jan-Ingvar
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Blomqvist, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Lipopolysaccharide-Induced Fever Depends on Prostaglandin E2 Production Specifically in Brain Endothelial Cells2012In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 153, no 10, p. 4849-4861Article in journal (Refereed)
    Abstract [en]

    Immune-induced prostaglandin E2 (PGE2) synthesis is critical for fever and other centrally elicited disease symptoms. The production of PGE2 depends on cyclooxygenase-2 and microsomal prostaglandin E synthase-1 (mPGES-1), but the identity of the cells involved has been a matter of controversy. We generated mice expressing mPGES-1 either in cells of hematopoietic or nonhematopoietic origin. Mice lacking mPGES-1 in hematopoietic cells displayed an intact febrile response to lipopolysaccharide, associated with elevated levels of PGE2 in the cerebrospinal fluid. In contrast, mice that expressed mPGES-1 only in hematopoietic cells, although displaying elevated PGE2 levels in plasma but not in the cerebrospinal fluid, showed no febrile response to lipopolysaccharide, thus pointing to the critical role of brain-derived PGE2 for fever. Immunohistochemical stainings showed that induced cyclooxygenase-2 expression in the brain exclusively occurred in endothelial cells, and quantitative PCR analysis on brain cells isolated by flow cytometry demonstrated that mPGES-1 is induced in endothelial cells and not in vascular wall macrophages. Similar analysis on liver cells showed induced expression in macrophages and not in endothelial cells, pointing at the distinct role for brain endothelial cells in PGE2 synthesis. These results identify the brain endothelial cells as the PGE2-producing cells critical for immune-induced fever.

  • 10.
    Halvarsson, Camilla
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Rörby, Emma
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Eliasson, Pernilla
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Lang, Stefan
    Lund Stem Cell Center, Lund University, Lund, Sweden.
    Soneji, Shamit
    Lund Stem Cell Center, Lund University, Lund, Sweden.
    Jönsson, Jan-Ingvar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Putative Role of Nuclear Factor-Kappa B But Not Hypoxia-Inducible Factor-1α in Hypoxia-Dependent Regulation of Oxidative Stress in Hematopoietic Stem and Progenitor Cells2019In: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 31, no 3, p. 211-226Article in journal (Refereed)
    Abstract [en]

    Aims: Adaptation to low oxygen of hematopoietic stem cells (HSCs) in the bone marrow has been demonstrated to depend on the activation of hypoxia-inducible factor (HIF)-1α as well as the limited production of reactive oxygen species (ROS). In this study, we aimed at determining whether HIF-1α is involved in protecting HSCs from ROS.

    Results: Oxidative stress was induced by DL-buthionine-(S,R)-sulfoximine (BSO)-treatment, which increases the mitochondrial ROS level. Hypoxia rescued Lineage-Sca-1+c-kit+ (LSK) cells from BSO-induced apoptosis, whereas cells succumbed to apoptosis in normoxia. Apoptosis in normoxia was inhibited with the antioxidant N-acetyl-L-cysteine or by overexpression of anti-apoptotic BCL-2. Moreover, stabilized expression of oxygen-insensitive HIFs could not protect LSK cells from oxidative stress-induced apoptosis at normoxia, neither could short hairpin RNA to Hif-1α inhibit the protective effects by hypoxia in LSK cells. Likewise, BSO treatment of LSK cells from Hif-1α knockout mice did not suppress the effects seen in hypoxia. Microarray analysis identified the nuclear factor-kappa B (NF-κB) pathway as a pathway induced by hypoxia. By using NF-κB lentiviral construct and DNA-binding assay, we found increased NF-κB activity in cells cultured in hypoxia compared with normoxia. Using an inhibitor against NF-κB activation, we could confirm the involvement of NF-κB signaling as BSO-mediated cell death was significantly increased in hypoxia after adding the inhibitor.

    Innovation: HIF-1α is not involved in protecting HSCs and progenitors to elevated levels of ROS on glutathione depletion during hypoxic conditions.

    Conclusion: The study proposes a putative role of NF-κB signaling as a hypoxia-induced regulator in early hematopoietic cells.

  • 11.
    Hamzic, Namik
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Tang, Yanjuan
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Eskilsson, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Kugelberg, Unn
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Ruud, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Jönsson, Jan-Ingvar
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Blomqvist, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Nilsberth, Camilla
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Interleukin-6 produced by non-hematopoietic cells mediates the lipopolysaccharide-induced febrile responseManuscript (preprint) (Other academic)
    Abstract [en]

    Interleukin-6 (IL-6) is critical for the lipopolysaccharide (LPS)-induced febrile response. However, the exact source(s) of IL-6 involved in regulating the LPS-elicited fever is still to be identified. One known source of IL-6 is hematopoietic cells, such as monocytes. To clarify the contribution of hematopoietically derived IL-6 to fever, we created chimeric mice expressing IL-6 either in cells of hematopoietic or, conversely, in cells of non-hematopoietic origin. This was performed by extinguishing hematopoetic cells in wild-type (WT) or IL-6 knockout (IL-6 KO) mice by whole-body irradiation and transplanting them with new stem cells. Mice lacking IL-6 in hematopoietic cells displayed normal fever to LPS and were found to have similar levels of IL-6 in the cerebrospinal fluid (CSF) and in plasma as well as similar expression of the IL-6 gene in the brain as WT mice. In contrast, IL-6 KO mice, with intact IL-6 production in cells of hematopoietic origin, only showed a minor elevation of the body temperature after peripheral LPS injection. While they displayed significantly elevated levels of IL-6 both in plasma and CSF compared with control mice, the increase was modest compared with that seen in LPS injected mice on WT background, the latter being approximately 20 times larger in magnitude. These results suggest that IL-6 of nonhematopoietic origin is the main source of IL-6 in LPS-induced fever, and that IL-6 produced by hematopoietic cells only plays a minor role.

  • 12.
    Hamzik, Namik
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Tang, Yan-juan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Eskilsson, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Örtegren Kugelberg, Unn
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Ruud, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Jönsson, Jan-Ingvar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Blomqvist, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Nilsberth, Camilla
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Interleukin-6 primarily produced by non-hematopoietic cells mediates the lipopolysaccharide-induced febrile response2013In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 33, p. 123-130Article in journal (Refereed)
    Abstract [en]

    Interleukin-6 (IL-6) is critical for the lipopolysaccharide (LPS)-induced febrile response. However, the exact source(s) of IL-6 involved in regulating the LPS-elicited fever is still to be identified. One known source of IL-6 is hematopoietic cells, such as monocytes. To clarify the contribution of hematopoietically derived IL-6 to fever, we created chimeric mice expressing IL-6 selectively either in cells of hematopoietic or, conversely, in cells of non-hematopoietic origin. This was performed by extinguishing hematopoietic cells in wild-type (WT) or IL-6 knockout (IL-6 KO) mice by whole-body irradiation and transplanting them with new stem cells. Mice on a WT background but lacking IL-6 in hematopoietic cells displayed normal fever to LPS and were found to have similar levels of IL-6 protein in the cerebrospinal fluid (CSF) and in plasma and of IL-6 mRNA in the brain as WT mice. In contrast, mice on an IL-6 KO background, but with intact IL-6 production in cells of hematopoietic origin, only showed a minor elevation of the body temperature after peripheral LPS injection. While they displayed significantly elevated levels of IL-6 both in plasma and CSF compared with control mice, the increase was modest compared with that seen in LPS injected mice on a WT background, the latter being approximately 20 times larger in magnitude. These results suggest that IL-6 of non-hematopoietic origin is the main source of IL-6 in LPS-induced fever, and that IL-6 produced by hematopoietic cells only plays a minor role.

  • 13. Hansson, Anders
    et al.
    Zetterblad, Jenny
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology.
    van Duren, Cathelijne
    Axelson, Håkan
    Jönsson, Jan-Ingvar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology.
    The Lim-only protein LMO2 acts as a positive regulator of erythroid differentiation2007In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 364, no 3, p. 675-681Article in journal (Refereed)
    Abstract [en]

    LMO2, a member of the LIM-only protein family, is essential for the regulation of hematopoietic stem cells and formation of erythroid cells. It is found in a transcriptional complex comprising LMO2, TAL1, E47, GATA-1, and LDB1 which regulates erythroid genes. While TAL1 has been shown to induce erythroid differentiation, LMO2 appears to suppress fetal erythropoiesis. In addition to LMO2, the closely related LMO4 gene is expressed in hematopoietic cells, but has unknown functions. Here we demonstrate that LMO2 and LMO4 are expressed at the same level in erythroid colonies from mouse bone marrow, implying a function in erythroid differentiation. However, while LMO2 induced erythroid differentiation, LMO4 had no such effect. Interestingly, both LMO2 and TAL1 were able to partially suppress myeloid differentiation, implying that they activate erythroid differentiation in uncommitted bone marrow progenitors. Both LMO2 and LMO4 interacted strongly to LDB1, which was required for their localization to the nucleus. © 2007 Elsevier Inc. All rights reserved.

  • 14.
    Hedlund, Anna
    et al.
    Linköping University, Department of Medical and Health Sciences, Radiology. Linköping University, Center for Medical Image Science and Visualization, CMIV. Linköping University, Faculty of Health Sciences.
    Ahrén, Maria
    Linköping University, Department of Physics, Chemistry and Biology, Surface Physics and Chemistry . Linköping University, Center for Medical Image Science and Visualization, CMIV. Linköping University, The Institute of Technology.
    Gustafsson, Håkan
    Linköping University, Center for Medical Image Science and Visualization, CMIV. Linköping University, Department of Medical and Health Sciences, Radiology. Linköping University, Faculty of Health Sciences.
    Abrikossova, Natalia
    Linköping University, Center for Medical Image Science and Visualization, CMIV. Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Warntjes, Marcel
    Linköping University, Center for Medical Image Science and Visualization, CMIV. Linköping University, Department of Medical and Health Sciences, Clinical Physiology. Linköping University, Faculty of Health Sciences.
    Jönsson, Jan-Ingvar
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Uvdal, Kajsa
    Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics . Linköping University, The Institute of Technology.
    Engström, Maria
    Linköping University, Center for Medical Image Science and Visualization, CMIV. Linköping University, Department of Medical and Health Sciences, Radiology. Linköping University, Faculty of Health Sciences.
    Detection of Gd2O3 Nanoparticles in Hematopoietic Cells for MRI Contrast EnhancementManuscript (preprint) (Other academic)
    Abstract [en]

    As the utility of magnetic resonance imaging (MRI) broadens, the importance of having specific and efficient contrast agents increases and there has been a huge development in the fields of molecular imaging and intracellular markers.

    Previous studies have shown that gadolinium oxide (Gd2O3 ) nanoparticles generate higher relaxivity than currently available Gd chelates. The Gd2O3 nanoparticles are also promising for MRI cell tracking. The aim of the present work was to study cell labeling with Gd2O3 nanoparticles and to improve techniques for monitoring hematopoietic stem cell migration by MRI.

    We studied particle uptake in two cell lines; the hematopoietic progenitor cell line Ba/F3 and the monocytic cell line THP-1. Cells were incubated with Gd2O3 nanoparticles as well as superparamagnetic iron oxide particles (SPIOs) for comparison. In addition, it was investigated whether the transfection agent protamine sulfate increased the particle uptake. Treated cells were examined by microscopic techniques, MRI and analyzed for particle content.

    Results showed that particles were intracellular, however in Ba/F3 only sparsely. The relaxation times were shortened with increasing particle concentration. Overall relaxivities, r1 and r2 for Gd2O3 nanoparticles in all cell samples measured were 5.1 ± 0.3 and 14.9 ± 0.7 (s-1mM-1) respectively. Goodness of fit was 0.97 in both cases. Protamine sulfate treatment increased the uptake in both Ba/F3 cells and THP-1 cells.

    Viability of treated cells was not significantly decreased and thus, we conclude that the use of Gd2O3 nanoparticles is suitable for this type of cell labeling by means of detecting and monitoring hematopoietic cells.

  • 15.
    Hedlund, Anna
    et al.
    Linköping University, Department of Medical and Health Sciences, Radiology. Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Faculty of Health Sciences.
    Ahrén, Maria
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, Faculty of Science & Engineering.
    Gustafsson, Håkan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medical and Health Sciences, Radiation Physics. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Abrikossova, Natalia
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, Faculty of Science & Engineering.
    Warntjes, Marcel
    Linköping University, Department of Medical and Health Sciences, Clinical Physiology. Linköping University, Faculty of Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Jönsson, Jan-Ivar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Medical and Physiological Chemistry.
    Uvdal, Kajsa
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, Faculty of Science & Engineering.
    Engström, Maria
    Linköping University, Department of Medical and Health Sciences, Radiology. Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Faculty of Health Sciences.
    Gd2O3 nanoparticles in hematopoietic cells for MRI contrast enhancement2011In: International journal of nano medicine, ISSN 1178-2013, Vol. 6, p. 3233-3240Article in journal (Refereed)
    Abstract [en]

    As the utility of magnetic resonance imaging (MRI) broadens, the importance of having specific and efficient contrast agents increases and in recent time there has been a huge development in the fields of molecular imaging and intracellular markers. Previous studies have shown that gadolinium oxide (Gd2O3) nanoparticles generate higher relaxivity than currently available Gd chelates: In addition, the Gd2O3 nanoparticles have promising properties for MRI cell tracking. The aim of the present work was to study cell labeling with Gd2O3 nanoparticles in hematopoietic cells and to improve techniques for monitoring hematopoietic stem cell migration by MRI. Particle uptake was studied in two cell lines: the hematopoietic progenitor cell line Ba/F3 and the monocytic cell line THP-1. Cells were incubated with Gd2O3 nanoparticles and it was investigated whether the transfection agent protamine sulfate increased the particle uptake. Treated cells were examined by electron microscopy and MRI, and analyzed for particle content by inductively coupled plasma sector field mass spectrometry. Results showed that particles were intracellular, however, sparsely in Ba/F3. The relaxation times were shortened with increasing particle concentration. Relaxivities, r1 and r2 at 1.5 T and 21°C, for Gd2O3 nanoparticles in different cell samples were 3.6–5.3 s-1 mM-1 and 9.6–17.2 s-1 mM-1, respectively. Protamine sulfate treatment increased the uptake in both Ba/F3 cells and THP-1 cells. However, the increased uptake did not increase the relaxation rate for THP-1 as for Ba/F3, probably due to aggregation and/or saturation effects. Viability of treated cells was not significantly decreased and thus, it was concluded that the use of Gd2O3 nanoparticles is suitable for this type of cell labeling by means of detecting and monitoring hematopoietic cells. In conclusion, Gd2O3 nanoparticles are a promising material to achieve positive intracellular MRI contrast; however, further particle development needs to be performed.

  • 16.
    Jönsson, Maria
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology.
    Engström, Maria
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology.
    Jönsson, Jan-Ingvar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology.
    FLT3 ligand regulates apoptosis through AKT-dependent inactivation of transcription factor FoxO32004In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 318, no 4, p. 899-903Article in journal (Refereed)
    Abstract [en]

    Proliferation, differentiation, and survival of hematopoietic cells are regulated by cytokines, acting through specific receptors. FLT3 ligand (FL) is one of the most important cytokines for regulation of the hematopoietic system, and its receptor FLT3 is expressed on both stem cells and progenitors. Regulation of Forkhead transcription factors has been described as an important mechanism to control apoptosis and cell cycle progression in hematopoietic progenitors. Here we report that FL induces AKT/PKB activation, which in turn phosphorylates and thereby inactivates the Forkhead protein FoxO3 in the progenitor cell line FDC-P1 stably expressing murine FLT3 receptor. Phosphorylation of AKT and FoxO3 was blocked by the PI-3 kinase inhibitor LY294002 but not by the MAP kinase inhibitor PD98059. Expression of a mutated FoxO3, in which all three inhibitory phosphorylation sites were mutated to alanine, led to rapid increase of apoptotic cells in the presence of FL. These results suggest that FL-induced regulation of apoptosis is executed by FoxO3.

  • 17.
    Karlsson, Anneli
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Nordigården, Amanda
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Jönsson, Jan-Ingvar
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology . Linköping University, Faculty of Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Bcl11b mutations identified in murine lymphomas increase the proliferation rate in hematopoietic progenitor cells2007In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 7, no 195, p. 195-Article in journal (Refereed)
    Abstract [en]

    Background: The telomeric region of mouse chromosome 12 has previously shown frequent allelic loss in murine lymphoma. The Bcl11b gene has been identified and suggested as a candidate tumor suppressor gene within this region. In this study, we aimed to elucidate whether Bcl11b is mutated in lymphomas with allelic loss, and whether the mutations we detected conferred any effect on cell proliferation and apoptosis.

    Methods: Mouse lymphomas induced by 1,3-butadiene or 2',3'-dideoxycytidine were analysed for mutations in the Bcl11b gene using single strand conformation analysis and direct DNA sequencing. Effects on cell proliferation by the detected mutations were studied by expressing wild-type and mutant Bcl11b in the cytokine-dependent hematopoietic progenitor cell line FDC-P1, lacking endogenous Bcl11b expression.

    Results: Missense and frameshift (FS) mutations were identified in 7 of 47 tumors (15%). Interestingly, all mutations were found between amino acids 778–844 which encode the three C-terminal DNA-binding zinc fingers. In FDC-P1 cells, wild-type Bcl11b suppressed cell proliferation, whereas the mutated versions (S778N, K828T, Y844C and FS823) enhanced proliferation several-fold.

    Conclusion: The genetic alterations detected in this study suggest that the three C-terminal zinc fingers of Bcl11b are important for the DNA-binding. Cell proliferation was suppressed by overexpression of wild-type Bcl11b but enhanced by mutant Bcl11b, indicating that these mutations may be an important contributing factor to lymphomagenesis in a subset of tumors.

  • 18.
    Martinsson, Klara
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Mousavi, Seyed Ali
    Rikshospital University Hospital, Oslo.
    Berg, Trond
    University of Oslo.
    Jönsson, Jan-Ingvar
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology . Linköping University, Faculty of Health Sciences.
    Hultman, Per
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Deficiency of Activating Fc gamma-Receptors Reduces Hepatic Clearance and Deposition of IC and Increases CIC Levels in Mercury-Induced Autoimmunity2010In: PLOS ONE, ISSN 1932-6203, Vol. 5, no 10Article in journal (Refereed)
    Abstract [en]

    Background: Inorganic mercury (Hg) induces a T-cell dependent, systemic autoimmune condition (HgIA) where activating Fc gamma-receptors (Fc gamma Rs) are important for the induction. In this study we examined the influence of activating Fc gamma Rs on circulating levels and organ localization of immune complexes (IC) in HgIA. Methods and Principal Findings: Mercury treated BALB/c wt mice showed a significant but modest increase of circulating IC (CIC) from day 12 until day 18 and day 35 for IgG2a- and IgG1- CIC, respectively. Mercury-treated mice lacking the transmembrane gamma-chain of activating Fc gamma Rs (FcR gamma(-/-)) had significantly higher CIC levels of both IgG1-CIC and IgG2a-CIC than wt mice during the treatment course. The hepatic uptake of preformed CIC was significantly more efficient in wt mice compared to Fc gamma R-/- mice, but also development of extrahepatic tissue IC deposits was delayed in FcR gamma(-/-) mice. After 35 days of Hg treatment the proportion of immune deposits, as well as the amounts was significantly reduced in vessel FcR gamma(-/-) mice compared to wt mice. Conclusions: We conclude that mice lacking functional activating Fc gamma Rs respond to Hg with increased levels and altered quality of CIC compared with wt mice. Lack of functional activating Fc gamma Rs delayed the elimination of CIC, but also significantly reduced extrahepatic tissue localization of CIC.

  • 19.
    Matsuwaki, Takashi
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Eskilsson, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Örtegren Kugelberg, Unn
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Jönsson, Jan-Ingvar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Blomqvist, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Interleukin-1 beta induced activation of the hypothalamus-pituitary-adrenal axis is dependent on interleukin-1 receptors on non-hematopoietic cells2014In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 40, p. 166-173Article in journal (Refereed)
    Abstract [en]

    The proinflammatory cytokine interleukin-1 beta (IL-beta) plays a major role in the signal transduction of immune stimuli from the periphery to the central nervous system, and has been shown to be an important mediator of the immune-induced stress hormone release. The signaling pathway by which IL-1 beta exerts this function involves the blood-brain-barrier and induced central prostaglandin synthesis, but the identity of the blood-brain-barrier cells responsible for this signal transduction has been unclear, with both endothelial cells and perivascular macrophages suggested as critical components. Here, using an irradiation and transplantation strategy, we generated mice expressing IL-1 type 1 receptors (IL-1 RI) either in hematopoietic or non-hematopoietic cells and subjected these mice to peripheral immune challenge with IL-beta. Following both intraperitoneal and intravenous administration of IL-beta, mice lacking IL-1R1 in hematopoietic cells showed induced expression of the activity marker c-Fos in the paraventricular hypothalamic nucleus, and increased plasma levels of ACTH and corticosterone. In contrast, these responses were not observed in mice with IL-1R1 expression only in hematopoietic cells. Immunoreactivity for IL-1R1 was detected in brain vascular cells that displayed induced expression of the prostaglandin synthesizing enzyme cyclooxygenase-2 and that were immunoreactive for the endothelial cell marker CD31, but was not seen in cells positive for the brain macrophage marker CD206. These results imply that activation of the HPA-axis by IL-1 beta is dependent on IL-1R1 s on non-hematopoietic cells, such as brain endothelial cells, and that IL-1R1 on perivascular macrophages are not involved.

  • 20.
    Mjösberg, Jenny
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Svensson, J
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology . Linköping University, Faculty of Health Sciences.
    Johansson, E
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology . Linköping University, Faculty of Health Sciences.
    Hellstrom, L
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology . Linköping University, Faculty of Health Sciences.
    Casas, Rosaura
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Jenmalm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Boij, R
    Ryhov Hospital.
    Matthiesen, L
    Helsingborg Hospital.
    Jönsson, Jan-Ingvar
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology . Linköping University, Faculty of Health Sciences.
    Berg, Göran
    Linköping University, Department of Clinical and Experimental Medicine, Obstetrics and gynecology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Gynecology and Obstetrics in Linköping.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Immunology and Transfusion Medicine.
    Systemic reduction of functionally suppressive CD4dimCD25highFoxp3+ T-regs in human second trimester pregnancy is induced by progesterone and 17 beta-estradiol2009In: Journal of Reproductive Immunology(ISSN 0165-0378), vol 81, issue 2, 2009, Vol. 81, no 2, p. 160-161Conference paper (Refereed)
    Abstract [en]

    CD4+CD25high regulatory T cells (Tregs) are implicated in maintenance of murine pregnancy. However, reports regarding circulating Treg frequencies in human pregnancy are inconsistent and the functionality and phenotype of these cells in pregnancy have not been clarified. The aim was to determine the frequency, phenotype and function of circulating Tregs in second trimester human pregnancy and the influence of progesterone and 17β-estradiol on Treg phenotype and frequency. Based on expression of Foxp3, CD127 and HLA-DR, as determined by multi-color flow cytometry, we defined a proper CD4dimCD25high Treg population and showed, in contrast to most previous reports, that this population was reduced in second trimester pregnancy. Unexpectedly, Foxp3 expression was decreased in the Treg, as well as in the CD4+ population. These changes could be replicated in an in vitro system resembling the pregnancy hormonal milieu, where 17β-estradiol, and in particular progesterone, induced, in line with the pregnancy situation, a reduction of CD4dimCD25highFoxp3+ cells in PBMC from non-pregnant women. By co-culturing FACS-sorted Tregs and autologous CD4+CD25- responder cells, we showed that Tregs from pregnant women still displayed the same suppressive capacity as non-pregnant women in terms of suppressing IL-2, TNF-α and IFN-γ secretion from responder cells while efficiently producing IL-4 and IL-10. Our findings support the view of hormones, particularly progesterone, as critical regulators of Tregs in pregnancy. Further, we suggest that in the light of the results of this study, early data on circulating Treg frequencies in pregnancy need re-evaluation.

  • 21.
    Mjösberg, Jenny
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences.
    Svensson, Judit
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences.
    Johansson, Emma
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences.
    Hellström, Lotta
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Department of Clinical and Experimental Medicine, Geriatric. Linköping University, Faculty of Health Sciences.
    Casas, Rosaura
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Jenmalm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Boij, Roland
    Ryhov Hospital, Jönköping, Sweden.
    Matthiesen, Leif
    Helsingborg Hospital, Helsingborg, Sweden.
    Jönsson, Jan-Ingvar
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Berg, Göran
    Linköping University, Department of Clinical and Experimental Medicine, Obstetrics and gynecology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Gynecology and Obstetrics in Linköping.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Immunology and Transfusion Medicine.
    Systemic reduction of functionally suppressive CD4dimCD25highFoxp3+ Tregs in human second trimester pregnancy is induced by progesterone and 17θ-estradiol2009In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 183, no 1, p. 759-769Article in journal (Refereed)
    Abstract [en]

    CD4+CD25high regulatory T cells (Tregs) are implicated in the maintenance of murine pregnancy. However, reports regarding circulating Treg frequencies in human pregnancy are inconsistent, and the functionality and phenotype of these cells in pregnancy have not been clarified. The aim of this study was to determine the frequency, phenotype, and function of circulating Tregs in the second trimester of human pregnancy and the influence of progesterone and 17β-estradiol on Treg phenotype and frequency. Based on expressions of Foxp3, CD127, and HLA-DR as determined by multicolor flow cytometry, we defined a proper CD4dimCD25high Treg population and showed, in contrast to most previous reports, that this population was reduced in second trimester of pregnancy. Unexpectedly, Foxp3 expression was decreased in the Treg, as well as in the CD4+ population. These changes could be replicated in an in vitro system resembling the pregnancy hormonal milieu, where 17β-estradiol, and in particular progesterone, induced, in line with the pregnancy situation, a reduction of CD4dimCD25highFoxp3+ cells in PBMC from nonpregnant women. By coculturing FACS-sorted Tregs and autologous CD4+CD25 responder cells, we showed that Tregs from pregnant women still displayed the same suppressive capacity as nonpregnant women in terms of suppressing IL-2, TNF-, and IFN- secretion from responder cells while efficiently producing IL-4 and IL-10. Our findings support the view of hormones, particularly progesterone, as critical regulators of Tregs in pregnancy. Furthermore, we suggest that in the light of the results of this study, early data on circulating Treg frequencies in pregnancy need reevaluation.

    The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

  • 22. Moller, C
    et al.
    Alfredsson, J
    Engström, Maria
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Wootz, H
    Xiang, Z
    Lennartsson, J
    Jönsson, Jan-Ingvar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology .
    Nilsson, G
    Stem cell factor promotes mast cell survival via inactivation of FOXO3a-mediated transcriptional induction and MEK-regulated phosphorylation of the proapoptotic protein Bim2005In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 106, no 4, p. 1330-1336Article in journal (Refereed)
    Abstract [en]

    Mast cells are found in tissues throughout the body where they play important roles in the regulation of inflammatory responses. One characteristic feature of mast cells is their longevity. Although it is well established that mast cell survival is dependent on stem cell factor (SCF), it has not been described how this process is regulated. Herein, we report that SCF promotes mast cell survival through inactivation of the Forkhead transcription factor FOXO3a (forkhead box, class O3A) and down-regulation and phosphorylation of its target Bim (Bcl-2 [B-cell lymphoma-2] interacting modulator of cell death), a Bcl-2 homology 3 (BH3)-only proapoptotic protein. SCF induced a rapid and transient phosphorylation of Akt (protein kinase B) and FOXO3a. SCF treatment prevented up-regulation of Bim protein expression and led to increased Bim phosphorylation. Bim phosphorylation was inhibited by PD98059 and LY294002 treatment, suggesting the involvement of mitogen-activated protein kinase kinase/mitogen-activated protein kinase (MEKJMAPK) and phosphatidylinositol 3 (PI3)-kinase pathways in this process. Overexpression of phosphorylation-deficient FOXO3a caused an up-regulation of Bim and induced mast cell apoptosis even in the presence of SCF. Mast cell apoptosis induced by the phosphorylation-deficient FOXO3a was attenuated in bim(-/-) mast cells. Because apoptosis is abnormally reduced in bim(-/-) mast cells, these data provide evidence that Akt-mediated inhibition of FOXO3a and its transcription target Bim provides an important mechanism by which SCF acts to prevent apoptosis in mast cells.

  • 23.
    Nordigården, Amanda
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Halvarsson, Camilla
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Tang, Yan-juan
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Druid, Pia
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Jönsson, Jan-Ingvar
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    A COMPARATIVE STUDY OF VARIOUS FLT3-ITD MUTATIONS ISOLATED FROM ACUTE MYELOID LEUKEMIA PATIENTS in EXPERIMENTAL HEMATOLOGY, vol 40, issue 8, pp S130-S1312012In: EXPERIMENTAL HEMATOLOGY, Elsevier , 2012, Vol. 40, no 8, p. S130-S131Conference paper (Refereed)
    Abstract [en]

    n/a

  • 24.
    Nordigården, Amanda
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology . Linköping University, Faculty of Health Sciences.
    Kraft, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology . Linköping University, Faculty of Health Sciences.
    Eliasson, Pernilla
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology . Linköping University, Faculty of Health Sciences.
    Labi, Verena
    Division of Developmental Immunology, Biocenter, Innsbruck Medical University.
    Lam, Eric W.-F
    Cancer Research-UK Labs, Department of Oncology, Imperial College London, Hammersmith Hospital Campus.
    Villunger, Andreas
    Division of Developmental Immunology, Biocenter, Innsbruck Medical University.
    Jönsson, Jan-Ingvar
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology . Linköping University, Faculty of Health Sciences.
    BH3-only protein Bim more critical than Puma in tyrosine kinase inhibitor-induced apoptosis of human leukemic cells and transduced hematopoietic progenitors carrying oncogenic FLT3.2009In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 113, no 10, p. 2302-2311Article in journal (Refereed)
    Abstract [en]

    Constitutively activating internal tandem duplications (ITD) of FLT3 (FMS-like tyrosine kinase 3) are the most common mutations in acute myeloid leukemia (AML) and correlate with poor prognosis. Receptor tyrosine kinase inhibitors targeting FLT3 have developed as attractive treatment options. Because relapses occur after initial responses, identification of FLT3-ITD–mediated signaling events are important to facilitate novel therapeutic interventions. Here, we have determined the growth-inhibitory and proapototic mechanisms of 2 small molecule inhibitors of FLT3, AG1295 or PKC412, in hematopoietic progenitor cells, human leukemic cell lines, and primary AML cells expressing FLT3-ITD. Inactivation of the PI3-kinase pathway, but not of Ras–mitogen-activated protein (MAP) kinase signaling, was essential to elicit cytotoxic responses. Both compounds induced up-regulation of proapoptotic BH3-only proteins Bim and Puma, and subsequent cell death. However, only silencing of Bim, or its direct transcriptional activator FOXO3a, abrogated apoptosis efficiently. Similar findings were made in bone marrow cells from gene-targeted mice lacking Bim and/or Puma infected with FLT3-ITD and treated with inhibitor, where loss of Puma only provided transient protection from apoptosis, but loss of Bim preserved clonal survival upon FLT3-ITD inhibition.

     

  • 25.
    Nordigården, Amanda
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Tang, Yanjuan
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Halvarsson, Camilla
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Jönsson, Jan-Ingvar
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    A comparative study of various FLT3-ITDs in relation to function and signalingManuscript (preprint) (Other academic)
    Abstract [en]

    Internal tandem duplications (ITD) in the FMS like tyrosine kinase (FLT3) receptor are one of the most common classes of mutations in acute myeloid leukemia (AML), which presence indicates a poor prognosis. Lengths of FLT3-ITD mutations found in patients can vary from 3 up to hundreds of nucleotides and may be located either in the juxtamembrane domain or the tyrosine kinase-1 domain (TKD1). There are contradicting opinions whether the length of the ITD has an impact on the clinical situation and whether tyrosines duplicated are of any significance for oncogenic signaling. Considering the substantial differences in lengths as well as the variability of start and end points of ITDs, we have performed a study of various FLT3-ITD mutations isolated from AML-patients. The ITD region from leukemic blasts of nine AML patients were sequenced and cloned by PCR into the human wildtype FLT3 cDNA, inserted to a retroviral GFP-containing vector. The hematopoietic progenitor cell line FDC-P1 was used to elucidate the impact of the different ITDs on growth, survival, signal transduction, and resistance to the FLT3-targeting inhibitor PKC412. Interestingly, the shortest and the longest ITDs were two of the three mutations that lead to the poorest survival of cells upon cytokine-deprivation, indicating that ITD size may not influence the transforming potential of cells. Furthermore one ITD that starts and ends relatively 3´ positioned, and comprises the 5´-part of the TKD1 showed both a survival advantage in starvation experiments and a significantly higher proliferation potential in comparison to several other mutations. Two other ITDs spanning this region, but with more 5´localized starting points, displayed less sensitivity to PKC412 treatment. However, this was not associated to STAT5 activity and MCL-1 upregulation as suggested by previous report. Taken together, this study suggests that different FLT3-ITD mutations may induce distinct signaling and response towards FLT3 targeting drugs, dependent of FLT3-ITD composition and not length.

  • 26.
    Nordigården, Amanda
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Zetterblad, Jenny
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Trinks, Cecilia
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Green, Henrik
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Eliasson, Pernilla
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Druid, Pia
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Lotfi, Kourosh
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pharmacology.
    Ronnstrand, Lars
    Lund University.
    Walz, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology UHL.
    Jönsson, Jan-Ingvar
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Irreversible pan-ERBB inhibitor canertinib elicits anti-leukaemic effects and induces the regression of FLT3-ITD transformed cells in mice2011In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 155, no 2, p. 198-208Article in journal (Refereed)
    Abstract [en]

    Recent findings have indicated that tyrosine kinase inhibitors (TKIs) targeting the ERBB receptor family display anti-leukaemic effects, despite the lack of receptor expression on human leukaemic cells. The occurrence of activating mutations in the gene encoding FMS-like tyrosine kinase 3 (FLT3) in patients with acute myeloid leukaemia (AML) has rendered inhibition of this receptor a promising therapeutic target. Due to possibility of cross-reactivity, we investigated the effect of the irreversible pan-ERBB inhibitor canertinib (CI-1033) on leukaemic cells expressing FLT3. The drug had anti-proliferative and apoptotic effects on primary AML cells and human leukaemic cell lines expressing mutated FLT3. In several AML patient samples, a blast cell population expressing FLT3-internal tandem duplication (ITD) was eradicated by canertinib. Canertinib inhibited receptor autophosphorylation and kinase activity of both mutated and FLT3 ligand stimulated wildtype FLT3, leading to inhibition of the PI3-kinase and MAP kinase pathways. Apoptotic induction was dependent on pro-apoptotic BH3-only protein BCL2L11/BIM because siRNA silencing attenuated apoptosis. Moreover, the drug induced regression of cells expressing FLT3-ITD in a murine in vivo-transplantation model at previously described tolerated doses. These results indicate that canertinib, as an irreversible TKI, could constitute a novel treatment regimen in patients with mutated or overexpressed FLT3.

  • 27.
    Saleiban, Amina
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Faxälv, Lars
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Claesson, Kjersti
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Jönsson, Jan-Ingvar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Osman, Abdimajid
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    miR-20b regulates expression of proteinase-activated receptor-1 (PAR-1) thrombin receptor in melanoma cells2014In: Pigment Cell & Melanoma Research, ISSN 1755-1471, E-ISSN 1755-148X, Vol. 27, no 3, p. 431-441Article in journal (Refereed)
    Abstract [en]

    The proteinase-activated receptor 1 (PAR-1) plays a central role in melanoma progression and its expression level is believed to correlate with the degree of cancer invasiveness. Here, we show that PAR-1 is post-transcriptionally regulated by miR-20b microRNA in human melanoma cells. PAR-1 was found to be expressed in metastatic melanoma cells but was barely detectable in primary melanoma. By transducing primary melanoma cells with a lentivirus containing a 3-UTR construct of PAR-1 mRNA, we could show that endogenous melanoma microRNAs interacted with PAR-1 3-UTR and silenced a fused luciferase reporter. Transfection of an inhibitor against miR-20b into primary melanoma cells reversed this process. Finally, transfection of miR-20b mimic into metastatic melanoma cells caused downregulation of the luciferase reporter. We conclude that miR-20b regulates expression of melanoma PAR-1 receptor, which may explain the differential expression of PAR-1 observed in human melanoma.

  • 28.
    Skoglund, Karin
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Boiso Moreno, Samuel
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Jönsson, Jan-Ingvar
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Green, Henrik
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Functional Characterization of ABCG2 Polymorphisms and Their Influence on Tyrosine Kinase Inhibitor Effects in Chronic Myeloid Leukemia Cells in BLOOD, vol 118, issue 21, pp 1491-14912011In: BLOOD, American Society of Hematology , 2011, Vol. 118, no 21, p. 1491-1491Conference paper (Refereed)
    Abstract [en]

    n/a

  • 29.
    Skoglund, Karin
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Boiso, Samuel
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Jönsson, Jan-Ingvar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Vikingsson, Svante
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Carlsson, Björn
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology.
    Green, Henrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Single-nucleotide polymorphisms of ABCG2 increase the efficacy of tyrosine kinase inhibitors in the K562 chronic myeloid leukemia cell line2014In: Pharmacogenetics & Genomics, ISSN 1744-6872, E-ISSN 1744-6880, Vol. 24, no 1, p. 52-61Article in journal (Refereed)
    Abstract [en]

    ObjectiveThe tyrosine kinase inhibitors (TKIs) used in the treatment of chronic myeloid leukemia are substrates for the efflux transport protein ATP-binding cassette subfamily G member 2 (ABCG2). Variations in ABCG2 activity might influence pharmacokinetics and therapeutic outcome of TKIs. The role of ABCG2 single-nucleotide polymorphisms (SNPs) in TKI treatment is not clear and functional in-vitro studies are lacking. The aim of this study was to investigate the consequences of ABCG2 SNPs for transport and efficacy of TKIs [imatinib, N-desmethyl imatinib (CGP74588), dasatinib, nilotinib, and bosutinib].Materials and methodsABCG2 SNPs 34Ggreater thanA, 421Cgreater thanA, 623Tgreater thanC, 886Ggreater thanC, 1574Tgreater thanG, and 1582Ggreater thanA were constructed from ABCG2 wild-type cDNA and transduced to K562 cells by retroviral gene transfer. Variant ABCG2 expression in cell membranes was evaluated and the effects of ABCG2 SNPs on transport and efficacy of TKIs were measured as the ability of ABCG2 variants to protect against TKI cytotoxicity.ResultsWild-type ABCG2 had a protective effect against the cytotoxicity of all investigated compounds except bosutinib. It was found that ABCG2 expression provided better protection against CGP74588 than its parent compound, imatinib. ABCG2 421Cgreater thanA, 623Tgreater thanC, 886Ggreater thanC, and 1574Tgreater thanG reduced cell membrane expression of ABCG2 and the protective effect of ABCG2 against imatinib, CGP74588, dasatinib, and nilotinib cytotoxicity.ConclusionThese findings show that the ABCG2 SNPs 421Cgreater thanA, 623Tgreater thanC, 886Ggreater thanC, and 1574Tgreater thanG increase the efficacy of investigated TKIs, indicating a reduced transport function that might influence TKI pharmacokinetics in vivo. Furthermore, the active imatinib metabolite CGP74588 is influenced by ABCG2 expression to a greater extent than the parent compound.

  • 30.
    Skoglund, Karin
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Moreno, Samuel Boiso
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Drug Research.
    Baytar, Maria
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Health Sciences.
    Jönsson, Jan-Ingvar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Gréen, Henrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    ABCB1 haplotypes do not influence transport or efficacy of tyrosine kinase inhibitors in vitro2013In: Pharmacogenomics and Personalized Medicine, ISSN 1178-7066, Vol. 6, p. 63-72Article in journal (Refereed)
    Abstract [en]

    Single-nucleotide polymorphisms (SNPs) in the gene coding for the efflux-transport protein ABCB1 (P-glycoprotein) are commonly inherited as haplotypes. ABCB1 SNPs and haplotypes have been suggested to influence the pharmacokinetics and therapeutic outcome of the tyrosine kinase inhibitor (TKI) imatinib, used for treatment of chronic myeloid leukemia (CML). However, no consensus has yet been reached with respect to the significance of variant ABCB1 in CML treatment. Functional studies of variant ABCB1 transport of imatinib as well as other TKIs might aid the interpretation of results from in vivo association studies, but are currently lacking. The aim of this study was to investigate the consequences of ABCB1 variant haplotypes for transport and efficacy of TKIs (imatinib, its major metabolite N-desmethyl imatinib [CGP74588], dasatinib, nilotinib, and bosutinib) in CML cells. Variant haplotypes - including the 61A>G, 1199G>A, 1236C>T, 1795G>A, 2677G>T/A, and 3435T>C SNPs - were constructed in ABCB1 complementary DNA and transduced to K562 cells using retroviral gene transfer. The ability of variant cells to express ABCB1 protein and protect against TKI cytotoxicity was investigated. It was found that dasatinib and the imatinib metabolite CGP74588 are effectively transported by ABCB1, while imatinib, nilotinib, and bosutinib are comparatively weaker ABCB1 substrates. None of the investigated haplotypes altered the protective effect of ABCB1 expression against TKI cytotoxicity. These findings imply that the ABCB1 haplotypes investigated here are not likely to influence TKI pharmacokinetics or therapeutic efficacy in vivo.

  • 31.
    Skoglund, Karin
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Moreno, Samuel Boiso
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Jönsson, Jan-Ingvar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Vikingsson, Svante
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Carlsson, Björn
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology.
    Gréen, Henrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Influence of variant ABCG2 on tyrosine kinase inhibitor transport and efficacy in the K562 chronic myeloid leukemia cell lineManuscript (preprint) (Other academic)
    Abstract [en]

    Objective: The tyrosine kinase inhibitors (TKIs) used in the treatment of chronic myeloid leukemia are substrates for the efflux transport protein ABCG2. Variations in ABCG2 activity might influence pharmacokinetics and therapeutic outcome of TKIs. The role of ABCG2 single nucleotide polymorphisms (SNPs) in TKI treatment is not clear and functional in vitro studies are lacking. The aim of this study was to investigate the consequences of ABCG2 SNPs for transport and efficacy of TKIs (imatinib, N-desmethyl imatinib (CGP74588), dasatinib, nilotinib and bosutinib). Methods: ABCG2 SNPs 34G>A, 421C>A, 623T>C, 886G>C, 1574T>G and 1582G>A were constructed from ABCG2 wild type cDNA and transduced to K562 cells by retroviral gene transfer. The ability of variant cells to express ABCG2 in the cell membrane and protect against TKI cytotoxicity was investigated. Results: Wild type ABCG2 had a protective effect against the cytotoxicity of all investigated compounds except bosutinib. It was found that ABCG2 expression provided a better protection against CGP74588 than its parent compound, imatinib. ABCG2 421C>A, 623T>C, 886G>C and 1574T>G reduced cell membrane expression of ABCG2 and the protective effect of ABCG2 against imatinib, CGP74588, dasatinib and nilotinib cytotoxicity. The most prominent effect was found for the 623T>C SNP which resulted in undetectable ABCG2 expression and low protection against TKI cytotoxicity. Conclusion: These findings show that the ABCG2 SNPs 421C>A, 623T>C, 886G>C and 1574T>G impair ABCG2 transport function and might influence TKI pharmacokinetics in vivo. Furthermore, the active imatinib metabolite CGP74588 is to a greater extent than the parent compound transported by ABCG2.

  • 32.
    Tang, Yan-juan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Halvarsson, Camilla
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Eliasson, Pernilla
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Jönsson, Jan-Ingvar
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Letter: Hypoxic and normoxic in vitro cultures maintain similar numbers of long-term reconstituting hematopoietic stem cells from mouse bone marrow2012In: Experimental Hematology, ISSN 0301-472X, E-ISSN 1873-2399, Vol. 40, no 11, p. 879-881Article in journal (Other academic)
    Abstract [en]

    n/a

  • 33.
    Tang, Yan-juan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Halvarsson, Camilla
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Nordigården, Amanda
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Kumar, Komal
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Åhsberg, Josefine
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Rörby, Emma
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Man Wong, Wan
    Lund University, Sweden.
    Jönsson, Jan-Ingvar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Coexpression of hyperactivated AKT1 with additional genes activated in leukemia drives hematopoietic progenitor cells to cell cycle block and apoptosis2015In: Experimental Hematology, ISSN 0301-472X, E-ISSN 1873-2399, Vol. 43, no 7, p. 554-564Article in journal (Refereed)
    Abstract [en]

    The phosphatidylinositol 3-kinase/AKT pathway is an integral component of signaling involved in the development of many cancers, including myeloid leukemias such as chronic myeloid leukemia and acute myeloid leukemia (AML). Increased AKT1 activity is frequently seen in AML patients, providing leukemic cells with growth and survival promoting signals. An important aspect of AKT1 function is its involvement in cellular metabolism and energy production. Under some circumstances, strong activation of AKT1 increases oxidative stress, which can cause apoptosis when cells progressively build up excess free radicals. This has been described in hematopoietic cells overexpressing activated AKT1; however, whether this is true in cells coexpressing other genetic events involved in leukemia is not known. This prompted us to investigate the effect of constitutively active AKT1 (myristoylated AKT1) in hematopoietic progenitor cells expressing constitutively active signal transducer and activator of transcription 5, Fms-related tyrosine kinase 3-internal tandem duplication, or antiapoptotic B-cell lymphoma 2. Surprisingly, myristoylated AKT1 was incompatible with proliferation driven by both signal transducer and activator of transcription 5 and Fms-related tyrosine kinase 3-internal tandem duplication, which triggered cell cycle block and apoptosis. Moreover, transplantable cells of B-cell lymphoma 2-transgenic mice were impaired in their engraftment ability to recipient mice when expressing hyperactivated AKT1. This Was linked to AKT1-mediated proapoptotic functions and not to impairment in homing to the bone marrow. Although cells expressing hyperactivated AKT1 displayed higher levels of reactive oxygen species both in vitro and in vivo, the addition of the antioxidant N-acetyl-L-cysteine significantly reduced apoptosis. Taken together, the results indicate that constitutive AKT1 activity is incompatible with growth- and survival-promoting ability of other activated genes in AML. Copyright (C) 2015 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc.

  • 34.
    Tang, Yanjuan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Halvarsson, Camilla
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Nordigården, Amanda
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Åhsberg, Josefine
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Wong, Wan Man
    Lund Strategic Center for Stem Cell Biology and Cell Therapy, Lund University, Lund, Sweden.
    Jönsson, Jan-Ingvar
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Hyperactivated AKT is incompatible with survival when coexpressed with additional oncogenes and drives hematopoietic stem and progenitor cells to cell cycle inhibition and apoptosisManuscript (preprint) (Other academic)
    Abstract [en]

    The PI3K-AKT signaling pathway plays an important role in cell growth and metabolism. Increased AKT activity is frequently seen in patients with acute myeloid leukemia (AML), providing leukemic cells with both growth-promoting and survival signals involved in the transformation process. In AML up to 30% of all patients carry activating mutations in the tyrosine kinase receptor FLT3, leading to activation of the PI3K/AKT pathway as well as STAT5. Here, we investigated the effect of hyperactivated AKT (myristylated AKT) by retroviral transfer to hematopoietic progenitor cells coexpressing STAT5, FLT3-ITD, or antiapoptotic Bcl-2. AKT was unable to relieve cytokine-dependence. Surprisingly, uncontrolled AKT activity was linked to accumulation of cells in the G0 stage of the cell cycle and increased cell numbers became apoptotic. Hyperactivated AKT was incompatible with STAT5-driven proliferation and triggered apoptosis. The same was true also in FLT3-ITDexpressing progenitor cells of transgenic mice. Transplantable hematopoietic stem cells of wildtype and Bcl-2 transgenic mice were impaired in their engraftment ability to recipient mice when expressing hyperactivated AKT. This was linked to AKT-mediated pro-apoptotic functions and not due to effects on homing or migration. Cells expressing hyperactivated AKT displayed higher levels of reactive oxygen species. However, the addition of the antioxidant N-acetyl-L-lysine significantly reduced apoptosis. Taken together, the results indicate that constitutive AKT activity is incompatible with the growth- and survivalpromoting ability of FLT3-ITD and its downstream targets. These findings may provide a novel tool to intervene with AKT activity in leukemia.

  • 35.
    Trinks, Cecilia
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Djerf, Emelie
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Hallbeck, Anna-Lotta
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology UHL.
    Jönsson, Jan-Ingvar
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Walz, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    The pan-ErbB receptor tyrosine kinase inhibitor canertinib induces ErbB-independent apoptosis in human leukemia (HL-60 and U-937) cells2010In: BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, ISSN 0006-291X, Vol. 393, no 1, p. 6-10Article in journal (Refereed)
    Abstract [en]

    Epidermal growth factor (EGF) receptor tyrosine kinase inhibitors have recently been shown to display anti-neoplastic effects in human malignant myeloid cells. Our study was initiated in order to determine the effect of the pan-ErbB receptor tyrosine kinase inhibitor, canertinib (CI-1033), on growth and survival of human leukemia (HL-60 and U-937) cells. We show that treatment of HL-60 and U-937 cells with canertinib significantly inhibits growth of both cell lines in a dose-dependent manner; half maximal effective dose (IC50) in HL-60 and U-937 cells was approximately 2.5 mu M and 1.0 mu M, respectively. Treatment with 2 mu M canertinib promoted a G(1) cell cycle arrest, whereas doses of 5 mu M or more induced apoptosis as determined by the Annexin V method and cleavage of poly-(ADP-ribose) polymerase (PARP). HL-60 and U-937 cells lacked EGF-receptor transcript but expressed ErbB2-4 mRNA as determined by RTPCR. However, none of the corresponding ErbB-receptor proteins could be detected by Western blot analysis. We conclude that canertinib induces apoptosis in HL-60 and U-937 cells devoid of functional ErbB1-4 receptors. Our results suggest that canertinib could be of potential clinical interest in the treatment of acute myeloid leukemia.

  • 36.
    Trinks, Cecilia
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Holmlund, Birgitta
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Jönsson, Jan-Ingvar
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Walz, Thomas M.
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology UHL.
    Human leukemic cell lines express a truncated intracellular 160 kDa ERBB2 receptorManuscript (preprint) (Other academic)
    Abstract [en]

    It has recently been demonstrated that ERBB specific tyrosine kinase inhibitors display antineoplastic activity in human leukemic cell devoid of functional ERBB receptors. The present study was undertaken in order to identify any putative target for these drugs. Flow cytometry experiments demonstrate the presence of an immunoreactive ERBB2 protein of intracellular localization and Western blot analysis visualized an ERBB2 protein of approximately 160 kDa. Exposing leukemia cells to tunicamycin did not alter the size of the truncated ERBB2 protein. The ERBB2 gene was alternative spliced with an absence of exon 5 containing the start codon for the full-length protein. In conclusion we demonstrate a nonglycosylated 160 kDa ERBB2-receptor protein with an alternative in-frame start codon in human leukemia cell lines.

  • 37.
    Trinks, Cecilia
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Severinsson, Emelie A.
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Holmlund, Birgitta
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Gréen, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Green, Henrik
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Jönsson, Jan-Ingvar
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Hallbeck, Anna-Lotta
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology UHL.
    Walz, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology UHL.
    The pan-ErbB tyrosine kinase inhibitor canertinib induces caspase-mediated cell death in human T-cell leukemia (Jurkat) cells2011In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 410, no 3, p. 422-427Article in journal (Refereed)
    Abstract [en]

    Canertinib is a novel ErbB-receptor inhibitor currently in clinical development for the treatment of solid tumors overexpressing ErbB-receptors. We have recently demonstrated that canertinib displays anti-proliferative and pro-apoptotic effects in human myeloid leukemia cells devoid of ErbB-receptors. The mechanism mediating these effects are however unknown. In this study, we show that canertinib is able to act as a multi-kinase inhibitor by inhibition of several intracellular kinases involved in T-cell signaling such as Akt, Erk1/2 and Zap-70, and reduced Lck protein expression in the human T-cell leukemia cell line Jurkat. Treatment with canertinib at a concentration of 2 mu M caused accumulation of Jurkat cells in the G(1) cell cycle phase and increased doses induced apoptosis in a time-dependent manner. Apoptotic signs of treated cells were detected by Annexin V staining and cleavage of PARP, caspase-3, -8, -9, -10 and Bid. A subset of the pro-apoptotic signals mediated by canertinib could be significantly reduced by specific caspase inhibitors. Taken together, these results demonstrate the dual ability of canertinib to downregulate important signaling pathways and to activate caspase-mediated intrinsic apoptosis pathway in human T-cell leukemia cells.

  • 38.
    Tsapogas, Panagiotis
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Zandi, Sasan
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Åhsberg, Josefine
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Zetterblad, Jenny
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Welinder, Eva
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Jönsson, Jan-Ingvar
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Mansson, Robert
    Lund University.
    Qian, Hong
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    IL-7 mediates Ebf-1-dependent lineage restriction in early lymphoid progenitors2011In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 118, no 5, p. 1283-1290Article in journal (Refereed)
    Abstract [en]

    eficiencies in the IL-7 signaling pathway result in severe disruptions of lymphoid development in adult mice. To understand more about how IL-7 deficiency impacts early lymphoid development, we have investigated lineage restriction events within the common lymphoid progenitor (CLP) compartment in IL-7 knockout mice. This revealed that although IL-7 deficiency had a minor impact on the development of LY6D(-) multipotent CLPs, the formation of the lineage restricted LY6D(+) CLP population was dramatically reduced. This was reflected in a low-level transcription of B-lineage genes as well as in a loss of functional B-cell commitment. The few Ly6D(+) CLPs developed in the absence of IL-7 displayed increased lineage plasticity and low expression of Ebf-1. Absence of Ebf-1 could be linked to increased plasticity because even though Ly6D(+) cells develop in Ebf-1-deficient mice, these cells retain both natural killer and dendritic cell potential. This reveals that IL-7 is essential for normal development of Ly6D(+) CLPs and that Ebf-1 is crucial for lineage restriction in early lymphoid progenitors.

  • 39.
    Verma, Deepti
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Lerm, Maria
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Eriksson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Fredriksson, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Occupational and Environmental Medicine. Linköping University, Faculty of Health Sciences.
    Andersson, Henrik
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Jönsson, Jan-Ingvar
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Särndahl, Eva
    Department of Clinical Medicine, School of Health & Medical Sciences, Örebro University, SE-701 82 Örebro, Sweden.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    The Q705K polymorphism in NLRP3 is a gain-of-function alteration leading to excessive interleukin-1β and IL-18 production2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 4Article in journal (Refereed)
    Abstract [en]

    Background: The Q705K polymorphism in NLRP3 has been implicated in several chronic inflammatory diseases. In this study, we determine the functional role of this commonly occurring polymorphism using an in-vitro system.

    Methods / Principle findings: NLRP3-WT and NLRP3-Q705K were retrovirally transduced into the human monocytic cell line THP-1, followed by the assessment of IL-1β and IL-18 levels in the cell culture supernatant. THP-1 cells expressing the above NLRP3 variants were sorted based upon Green Fluorescent Protein (GFP) expression. Cytokine response to alum (one of the most widely used adjuvants in vaccines) in the cells stably expressing NLRP3-WT and NLRP3-Q705K were determined. IL-1β and IL-18 levels were found to be elevated in THP-1 cells transduced with NLRP3-Q705K compared to the NLRP3-WT. Upon exposure to alum, THP-1 cells stably expressing NLRP3-Q705K displayed an increased production of IL-1β, IL-18 and TNF-α, in a caspase-1 and IL-1 receptor-dependent manner.

    Conclusions: Collectively, these findings show that the Q705K polymorphism in NLRP3 is a gain-of-function alteration leading to an overactive NLRP3 inflammasome. The option of IL-1β blockade may be considered in patients with chronic inflammatory disorders that are unresponsive to conventional treatments.

  • 40.
    Wiechec, Emilia
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Tiefenböck Hansson, Katharina
    Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Otorhinolaryngology in Linköping.
    Alexandersson, Lisa
    Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Otorhinolaryngology in Linköping.
    Jönsson, Jan-Ingvar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Roberg, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Otorhinolaryngology in Linköping.
    Hypoxia Mediates Differential Response to Anti-EGFR Therapy in HNSCC Cells.2017In: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 18, no 5Article in journal (Refereed)
    Abstract [en]

    Despite advances in the head and neck squamous cell carcinoma (HNSCC) treatment modalities, drug resistance and cancer recurrence are often reported. Hypoxia signaling through hypoxia-inducible factor 1 (HIF-1) promotes angiogenesis and metastasis by inducing epithelial-mesenchymal-transition (EMT). The aim of this study was to evaluate the impact of hypoxia on response to therapy as well as EMT and expression of stem cell markers in HNSCC cells. Five HNSCC cell lines (UT-SCC-2, UT-SCC-14, LK0412, LK0827, and LK0923) were selected for this study. The treatment sensitivity for radiation, cisplatin, cetuximab, and dasatinib was assessed by crystal violet assay. Gene expression of EMT and cancer stem cell (CSC) markers as well as protein level of EGFR signaling molecules were analyzed by qPCR and western blotting, respectively. Unlike UT-SCC-14 and LK0827, the LK0412 cell line became significantly more sensitive to cetuximab in hypoxic conditions. This cetuximab sensitivity was efficiently reversed after suppression of HIF-1α with siRNA. Additionally, hypoxia-induced EMT and expression of stem cell markers in HNSCC cells was partially revoked by treatment with cetuximab or knockdown of HIF-1α. In summary, our study shows that hypoxia might have a positive influence on the anti-EGFR therapy effectiveness in HNSCC. However, due to heterogeneity of HNSCC lesions, targeting HIF-1α may not be sufficient to mediate such a response. Further studies identifying a trait of hypoxia-specific response to cetuximab in HNSCC are advisable.

  • 41.
    Yang, Lie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Olsson, Birgit
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Pfeifer, Daniella
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Jönsson, J-I
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Zhou, Z-G
    Sichuan University.
    Jiang, X
    Sichuan University.
    Fredriksson, Bengt-Arne
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Zhang, H
    University of Skovde.
    Sun, Xiao-Feng
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Knockdown of peroxisome proliferator-activated receptor-beta induces less differentiation and enhances cell-fibronectin adhesion of colon cancer cells2010In: ONCOGENE, ISSN 0950-9232, Vol. 29, no 4, p. 516-526Article in journal (Refereed)
    Abstract [en]

    The role of peroxisome proliferator-activated receptor-beta/delta (PPAR-beta/delta) in the pathogenesis of colon cancer remains highly controversial. This study specifically silenced the PPAR-beta expression in three colon cancer cell lines with different metastatic potentials. Although PPAR-beta knockdown resulted in more malignant morphological changes, bigger colony sizes and lower carcinoembryonic antigen (CEA) secretion, and enhanced the cell-fibronectin adhesion, cell invasion and migration were unaffected. These effects were stronger in poorly metastatic cell lines compared with highly metastatic ones. Simultaneously, PPAR-beta knockdown decreased the mRNAs encoding adipocyte differentiation-related protein and liver fatty acid binding protein, and increased the mRNA of ILK, whereas the mRNAs encoding integrin-beta 1 and angiopoietin-like 4 were unchanged. Using immunohistochemistry, we determined that the intensity of PPAR-beta expression was stronger in rectal cancers with better differentiation than in those with poor differentiation, and was stronger in early-stage tumors than in advanced ones. Together, these findings consistently indicate that PPAR-beta may facilitate differentiation and inhibit the cell-fibronectin adhesion of colon cancer, having a role as an inhibitor in the carcinogenesis and progression of colorectal cancer. Interestingly, PPAR-beta seems to have a more important role in poorly metastatic cells than in highly metastatic ones.

  • 42.
    Åhsberg, Josefine
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Tsapogas, Panagiotis
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Qian, Hong
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Zetterblad, Jenny
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Zandi, Sasan
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Mansson, Robert
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Jönsson, Jan-Ingvar
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Interleukin-7-induced Stat-5 Acts in Synergy with Flt-3 Signaling to Stimulate Expansion of Hematopoietic Progenitor Cells2010In: JOURNAL OF BIOLOGICAL CHEMISTRY, ISSN 0021-9258, Vol. 285, no 47, p. 36275-36284Article in journal (Refereed)
    Abstract [en]

    The development of lymphoid cells from bone marrow progenitors is dictated by interplay between internal cues such as transcription factors and external signals like the cytokines Flt-3 ligand and Il-7. These proteins are both of large importance for normal lymphoid development; however, it is unclear if they act in direct synergy to expand a transient Il-7R(+)Flt-3(+) population or if the collaboration is created through sequential activities. We report here that Flt-3L and Il-7 synergistically stimulated the expansion of primary Il-7R(+)Flt-3(+) progenitor cells and a hematopoietic progenitor cell line ectopically expressing the receptors. The stimulation resulted in a reduced expression of pro-apoptotic genes and also mediated survival of primary progenitor cells in vitro. However, functional analysis of single cells suggested that the anti-apoptotic effect was additive indicating that the synergy observed mainly depends on stimulation of proliferation. Analysis of downstream signaling events suggested that although Il-7 induced Stat-5 phosphorylation, Flt-3L caused activation of the ERK and AKT signaling pathways. Flt-3L could also drive proliferation in synergy with ectopically expressed constitutively active Stat-5. This synergy could be inhibited with either receptor tyrosine kinase or MAPK inhibitors suggesting that Flt-3L and Il-7 act in synergy by activation of independent signaling pathways to expand early hematopoietic progenitors.

1 - 42 of 42
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf