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  • 1.
    Blomgran, Robert
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Zheng, Limin
    State Key Laboratory of Biocontrol, College of Life Sciences, Sun Yatsen (Zhongshan) University, Guangzhou, China.
    Stendahl, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Cathepsin-cleaved Bid promotes apoptosis in human neutrophils via oxidative stress-induced lysosomal membrane permeabilization2007In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 81, p. 1213-1223Article in journal (Refereed)
    Abstract [en]

    Lysosomal membrane permeabilization (LMP) is emerging as an important regulator of cell apoptosis. Human neutrophils are highly granulated phagocytes, which respond to pathogens by exhibiting increased production of reactive oxygen species (ROS) and lysosomal degranulation. In a previous study, we observed that intracellular, nonphagosomal generation of ROS triggered by adherent bacteria induced ROS-dependent neutrophil apoptosis, whereas intraphagosomal production of ROS during phagocytosis had no effect. In the present study, we measured lysosomal membrane stability and leakage in human neutrophils and found that adherent, noningested, Type 1-fimbriated Escherichia coli bacteria induced LMP rapidly in neutrophils. Pretreatment with the NADPH oxidase inhibitor diphenylene iodonium markedly blocked the early LMP and apoptosis in neutrophils stimulated with Type 1-fimbriated bacteria but had no effect on the late LMP seen in spontaneously apoptotic neutrophils. The induced lysosomal destabilization triggered cleavage of the proapoptotic Bcl-2 protein Bid, followed by a decrease in the antiapoptotic protein Mcl-1. Involvement of LMP in initiation of apoptosis is supported by the following observations: Bid cleavage and the concomitant drop in mitochondrial membrane potential required activation of cysteine-cathepsins but not caspases, and the differential effects of inhibitors of cysteine-cathepsins and cathepsin D on apoptosis coincided with their ability to inhibit Bid cleavage in activated neutrophils. Together, these results indicate that in microbe-induced apoptosis in neutrophils, ROS-dependent LMP represents an early event in initiation of the intrinsic apoptotic pathway, which is followed by Bid cleavage, mitochondrial damage, and caspase activation.

  • 2.
    Cedergren, Jan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology . Linköping University, Faculty of Health Sciences.
    Forslund, Tony
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Sundqvist, Tommy
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology . Linköping University, Faculty of Health Sciences.
    Oxidative activation of human neutrophils by type-1-collagen-coated particles is influenced by nitric oxide production and modulated by endogenous arginase2007In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673Article in journal (Refereed)
  • 3.
    Forsberg, Maria
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Blomgran, Robert
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Lem, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Särndahl, Eva
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Sebti, Said M.
    Drug Discovery Program, H. Lee Moffitt Cancer Center & Research Institute, Department of Oncology, University of South Florida, Tampa.
    Hamilton, Andrew
    Department of Chemistry, Yale University, New Haven, Connecticut .
    Stendahl, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Zheng, Limin
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Differential effects of invasion by and phagocytosis of Salmonella typhimurium on apoptosis in human macrophages: potential role of Rho–GTPases and Akt2003In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 74, no 4, p. 620-629Article in journal (Refereed)
    Abstract [en]

    In addition to direct activation of caspase-1 and induction of apoptosis by SipB, invasive Salmonella stimulates multiple signaling pathways that are key regulators of host cell survival. Nevertheless, little is known about the relative contributions of these pathways to Salmonella-mediated death of macrophages. We studied human monocytic U937 cells and found that apoptosis was induced by invading wild-type Salmonella typhimurium but not by phagocytosed, serum-opsonized, noninvasive Salmonella mutants. Pretreating U937 cells with inhibitors of tyrosine kinases or phosphatidylinositol-3 kinase (PI-3K) completely blocked phagocytosis of opsonized Salmonella mutants but did not affect invasion by wild-type Salmonella or the apoptosis caused by invasion. However, pretreatment with GGTI-298, a geranylgeranyltransferase-1 inhibitor that prevents prenylation of Cdc42 and Rac1, suppressed Salmonella-induced apoptosis by ∼70%. Transduction of Tat fusion constructs containing dominant-negative Cdc42 or Rac1 significantly inhibited Salmonella-induced cell death, indicating that the cytotoxicity of Salmonella requires activation of Cdc42 and Rac. In contrast to phagocytosis of opsonized bacteria, invasion by S. typhimurium stimulated Cdc42 and Rac1, regardless of the activities of tyrosine- or PI-3K. Moreover, Salmonella infection activated Akt protein in a tyrosine-kinase or PI-3K-dependent manner, and a reduced expression of Akt by antisense transfection rendered the cells more sensitive to apoptosis induced by opsonized Salmonella. These results indicate that direct activation of Cdc42 and Rac1 by invasive Salmonella is a prerequisite of Salmonella-mediated death of U937 cells, whereas the simultaneous activation of Akt by tyrosine kinase and PI-3K during receptor-mediated phagocytosis protects cells from apoptosis.

  • 4.
    Forsberg, Maria
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Druid, Pia
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Zheng, Limin
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Stendahl, Olle
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Särndahl, Eva
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Activation of Rac2 and Cdc42 on Fc and complement receptor ligation in human neutrophils2003In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 74, no 4, p. 611-619Article in journal (Refereed)
    Abstract [en]

    Phagocytosis is a complex process engaging a concerted action of signal-transduction cascades that leads to ingestion, subsequent phagolysosome fusion, and oxidative activation. We have previously shown that in human neutrophils, C3bi-mediated phagocytosis elicits a significant oxidative response, suggesting that activation of the small GTPase Rac is involved in this process. This is contradictory to macrophages, where only Fc receptor for immunoglobulin G (FcγR)-mediated activation is Rac-dependent. The present study shows that engagement of the complement receptor 3 (CR3) and FcγR and CR3- and FcγR-mediated phagocytosis activates Rac, as well as Cdc42. Furthermore, following receptor-engagement of the CR3 or FcγRs, a downstream target of these small GTPases, p21-activated kinase, becomes phosphorylated, and Rac2 is translocated to the membrane fraction. Using the methyltransferase inhibitors N-acetyl-S-farnesyl-L-cysteine and N-acetyl-S-geranylgeranyl-L-cysteine, we found that the phagocytic uptake of bacteria was not Rac2- or Cdc42-dependent, whereas the oxidative activation was decreased. In conclusion, our results indicate that in neutrophils, Rac2 and Cdc42 are involved in FcR- and CR3-induced activation and for properly functioning signal transduction involved in the generation of oxygen radicals.

  • 5.
    Ghavami, Saeid
    et al.
    Tarbiat Modarres University, Tehran, Iran.
    Kerkhoff, C.
    Institute of Experimental Dermatology, Münster, Germany .
    Los, Marek Jan
    Institute of Experimental Dermatology, Münster, Germany .
    Hashemi, M.
    Tarbiat Modarres University, Tehran, Iran.
    Sorg, C.
    Institute of Experimental Dermatology, Münster, Germany .
    Karami-Tehrani, F.
    Tarbiat Modarres University, Tehran, Iran.
    Mechanism of apoptosis induced by S100A8/A9 in colon cancer cell lines: the role of ROS and the effect of metal ions2004In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 76, no 1, p. 169-175Article in journal (Refereed)
    Abstract [en]

    The protein complex S100A8/A9, abundant in the cytosol of neutrophils, is secreted from the cells upon cellular activation and induces apoptosis in tumor cell lines and normal fibroblasts in a zinc-reversible manner. In the present study, we present evidence that the S100A8/A9 also exerts its apoptotic effect by a zinc-independent mechanism. Treatment of the colon carcinoma cells with different concentrations of human SI00A8/A9 or the metal ion chelator diethylenetriaminepentacetic acid (DTPA) resulted in a significant increase of cell death. Annexin V/phosphatidylinositol and Hoechst 33258 staining revealed that cell death was mainly of the apoptotic type. A significant increase in the activity of caspase-3 and -9 was observed in both cell lines after treatment. Caspase-8 activation was negligible in both cell lines. The cytotoxicity/apoptotic effect of human SI00A8/A9 and DTPA was inhibited significantly 2 2 (P<0.05) by Zn+2 and Cu+2, more effectively than by Ca2+ and Mg2+. The antioxidant N-acetyl-L-cysteine inhibited the cytotoxicity/apoptotic effect of SI00A8/A9 and DTPA. However, as a result of the different time-courses of both agents and that the S100A8/A9-induced apoptosis was not completely reversed, we conclude that S100A8/A9 exerts its apoptotic effect on two colon carcinoma cell lines through a dual mechanism: one via zinc exclusion from the target cells and the other through a yet-undefined mechanism, probably relaying on the cell-surface receptor(s).

  • 6.
    Ghavami, Saeid
    et al.
    Department of Biochemistry and Medical Genetics, Manitoba Institute of Cell Biology, Cancer Care Manitoba, Winnipeg, Manitoba, Canada.
    Rashedi, Iran
    Manitoba Institute of Cell Biology and Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada.
    Dattilo, Brian M.
    Departments of Biochemistry, Physics and Chemistry, Center for Structural Biology, Vanderbilt University, Nashville, Tennessee, USA;.
    Eshraghi, Mehdi
    Manitoba Institute of Cell Biology and Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada.
    Chazin, Walter J.
    Departments of Biochemistry, Physics and Chemistry, Center for Structural Biology, Vanderbilt University, Nashville, Tennessee, USA;.
    HashemI, Mohammad
    Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Science, Zahedan, Iran.
    Wesselborg, Sebastian
    Department of Internal Medicine I, University of Tübingen, Tübingen, Germany; and BioApplications Enterprises, Winnipeg, Manitoba, Canada.
    Kerkhoff, Claus
    Institute of Experimental Dermatology, Münster, Germany.
    Los, Marek Jan
    BioApplications Enterprises, Winnipeg, MB, Canada.
    S100A8/A9 at low concentration promotes tumor cell growth via RAGE ligation and MAP kinase-dependent pathway2008In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 83, no 6, p. 1484-1492Article in journal (Refereed)
    Abstract [en]

    The complex formed by two members of the S100 calcium-binding protein family, S100A8/A9, exerts apoptosis-inducing activity against various cells, especially tumor cells. Here, we present evidence that S100A8/A9 also has cell growth-promoting activity at low concentrations. Receptor of advanced glycation end product (RAGE) gene silencing and cotreatment with a RAGE-specific blocking antibody revealed that this activity was mediated via RAGE ligation. To investigate the signaling pathways, MAPK phosphorylation and NF-κB activation were characterized in S100A8/A9-treated cells. S100A8/A9 caused a significant increase in p38 MAPK and p44/42 kinase phosphorylation, and the status of stress-activated protein kinase/JNK phosphorylation remained unchanged. Treatment of cells with S100A8/A9 also enhanced NF-κB activation. RAGE small interfering RNA pretreatment abrogated the S100A8/A9-induced NF-κB activation. Our data indicate that S100A8/A9-promoted cell growth occurs through RAGE signaling and activation of NF-κB.

  • 7.
    Karlsson, Thommie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Glogauer, Michael
    University of Toronto.
    Ellen, Richard P
    University of Toronto.
    Loitto, Vesa
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Magnusson, Karl-Eric
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Magalhaes, Marco A O
    University of Toronto.
    Aquaporin 9 phosphorylation mediates membrane localization and neutrophil polarization2011In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 90, no 5, p. 963-973Article in journal (Refereed)
    Abstract [en]

    Neutrophils are of prime importance in the host innate defense against invading microorganisms by using two primary mechanisms-locomotion toward and phagocytosis of the prey. Recent research points to pivotal roles for water channels known as AQPs in cell motility. Here, we focused on the role of AQP9 in chemoattractant-induced polarization and migration of primary mouse neutrophils and neutrophil-like HL60 cells. We found that AQP9 is phosphorylated downstream of fMLFR or PMA stimulation in primary human neutrophils. The dynamics of AQP9 were assessed using GFP-tagged AQP9 constructs and other fluorescent markers through various live-cell imaging techniques. Expression of WT or the phosphomimic S11D AQP9 changed cell volume regulation as a response to hyperosmotic changes and enhanced neutrophil polarization and chemotaxis. WT AQP9 and S11D AQP9 displayed a very dynamic distribution at the cell membrane, whereas the phosphorylation-deficient S11A AQP9 failed to localize to the plasma membrane. Furthermore, we found that Rac1 regulated the translocation of AQP9 to the plasma membrane. Our results show that AQP9 plays an active role in neutrophil volume regulation and migration. The display of AQP9 at the plasma membrane depends on AQP9 phosphorylation, which appeared to be regulated through a Rac1-dependent pathway.

  • 8.
    Karlsson, Thommie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Musse, Farah
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Magnusson, Karl-Eric
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Vikström, Elena
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    N-Acylhomoserine lactones are potent neutrophil chemoattractants that act via calcium mobilization and actin remodeling2012In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 91, no 1, p. 15-26Article in journal (Refereed)
    Abstract [en]

    In gram-negative bacteria, cell-cell communication based on HSL QS molecules is known to coordinate the production of virulence factors and biofilms. These bacterial signals can also modulate human immune cell behavior. Using a Transwell migration assay, we found that human primary neutrophils are strongly stimulated by 3O-C(12)-HSL and -C(10)-HSL but not C(4)-HSL in a concentration-dependent manner. Moreover, 3O-C(12)-HSL and -C(10)-HSL activate PLC gamma 1 but not -gamma 2, mobilize intracellular calcium, and up-regulate IP(3)R. These changes were paralleled by F-actin accumulation, primarily in the leading edge of neutrophils, as evidenced by phalloidin staining and confocal microscopy. F- and G-actin isolation and quantification by immunoblotting revealed that the F/G-actin ratio was increased significantly after treatment with all three HSLs. Furthemore, 3O-C(12)-HSL- and 3O-C(10)-HSL treatment resulted in phosphorylation of Rac1 and Cdc42. In contrast, C(4)-HSL had negligible influence on the phosphorylation status of PLC and Rac1/Cdc42 and failed to attract neutrophils and induce calcium release. The calcium inhibitor thapsigargin, which blocks ER calcium uptake, strongly prevented neutrophil migration toward 3O-C(12)-HSL and -C(10)-HSL. These findings show that the bacterial QS molecules 3O-C(12)-HSL and -C(10)-HSL may attract human neutrophils to the sites of bacterial infection and developing biofilms. Indeed, recognition of HSL QS signals by neutrophils may play a critical role in their recruitment during infections.

  • 9.
    Loitto, Vesa-Matti
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Forslund, Tony
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Sundqvist, Tommy
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Magnusson, Karl-Eric
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Gustafsson, Mikael
    Linköping University, Department of Medicine and Care. Linköping University, Faculty of Health Sciences.
    Neutrophil leukocyte motility requires directed water influx2002In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 71, no 2, p. 212-222Article in journal (Refereed)
    Abstract [en]

    The ability of neutrophils to sense and move to sites of infection is essential for our defense against pathogens. For motility, lamellipodium extension and stabilization are prerequisites, but how cells form such membrane protrusions is still obscure. Using contrast-enhanced video microscopy and Transwell® assays, we show that water-selective aquaporin channels regulate lamellipodium formation and neutrophil motility. Addition of anti-aquaporin-9 antibodies, HgCl2, or tetraethyl ammonium inhibited the function(s) of the channels and blocked motility-related shape changes. On human neutrophils, aquaporin-9 preferentially localized to the cell edges, where N-formyl peptide receptors also accumulated, as assessed with fluorescence microscopy. To directly visualize water fluxes at cell edges, cells were loaded with high dilution-sensitive, self-quenching concentrations of fluorophore. In these cells, motile regions always displayed increased fluorescence compared with perinuclear regions. Our observations provide the first experimental support for motility models where water fluxes play a pivotal role in cell-volume increases accompanying membrane extensions.

  • 10.
    Lundqvist-Gustafsson, Helen
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Bengtsson, Torbjörn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology.
    Activation of the granule pool of the NADPH oxidase accelerates apoptosis in human neutrophils. 1999In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 65, p. 196-204Article in journal (Refereed)
  • 11.
    Lundqvist-Gustafsson, Helen
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Norrman, Sara
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Nilsson, Jessica
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Wilsson, Åsa
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Involvement of p38-mitogen-activated protein kinase in staphylococcus aureus-induced neutrophil apoptosis2001In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 70, no 4, p. 642-648Article in journal (Refereed)
    Abstract [en]

    Apoptosis occurred in human neutrophils within an hour of exposure to viable serumopsonized Staphylococcus aureus, as indicated by appearance of cells with condensed nuclei, fragmented DNA, and increased phosphatidylserine exposure. In contrast, serum-opsomized, heat-killed S. aureus did not induce apoptosis. This discrepancy could not be explained by differences in bacterial uptake or total NADPH-oxidase activity. Suppressing phagocytosis by pretreating the neutrophils with cytochalasin b or by using nonopsonized bacteria did not prevent apoptosis. A supernatant from bacteria grown for 2 h in nutrient broth had a strong proapoptotic influence that was abrogated by heat treatment. Exposure to viable S. aureus or supernatant also led to activation of p38-mitogen-activated protein kinase in the neutrophils. Inhibition of this kinase with SB203580 reduced the apoptosis-inducing capacity of both bacteria and supernatant. We conclude that S. aureus activates p38-mitogen-activated protein kinase in neutrophils and induces apoptosis, probably mediated by a bacteria-derived soluble factor(s).

  • 12.
    Majeed, Meytham
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology.
    Caveggion, E
    Lowell, CA
    Berton, G
    Role of Src kinases and Syk in Fc? receptor-mediated phagocytosis and phagosome-lysosome fusion2001In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 70, no 5, p. 801-811Article in journal (Refereed)
    Abstract [en]

    Phagocytosis is increased by Fc? receptors (Fc?Rs), and studies with syk-1- macrophages demonstrated that Syk kinase is required for Fc?TR phagocytosis. Similar studies with macrophages lacking the Src family kinases Hck, Fgr, and Lyn showed that these kinases are not required for phagocytosis but that they enhance the rate of particle engulfment. In this report we show that both wild-type and hck-1- fgr-1- macrophages expressed Fyn, Src, and Yes and that these kinases were activated on ingestion of immunoglobulin G (IgG)-coated particles and redistributed, together with Syk, to actin-rich phagocytic cups and the phagosomal membrane. At doses blocking IgG-dependent phagocytosis, the tyrosine kinase inhibitors PP1 and piceatannol inhibited both Src family kinase and Syk activities, as well as their redistribution to actin-rich phagocytic cups. Hck, Fgr, and Lyn were dispensable for lysosome-phagosome fusion (PLF) induced by IgG-coated particles. However, PP1 or piceatannol hampered unopsonized yeast-induced PLF despite the fact that they did not block yeast internalization.

  • 13.
    Mera, Simona
    et al.
    Sahlgrenska University Hospital, Göteborg, Sweden.
    Magnusson, Mattias
    Sahlgrenska University Hospital, Göteborg, Sweden.
    Tarkowski, Andrej
    Sahlgrenska University Hospital, Göteborg, Sweden.
    Bokarewa, Maria
    Sahlgrenska University Hospital, Göteborg, Sweden.
    Extracellular survivin up-regulates adhesion molecules on the surface of leukocytes changing their reactivity pattern2008In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 83, no 1, p. 149-155Article in journal (Refereed)
    Abstract [en]

    Rheumatoid arthritis (RA) is an autoimmune disease with joints as a principal target of inflammation. We have shown recently that the extracellular expression of the antiapoptotic protein survivin is associated with a destructive course of RA. Here, we address the potential impact of extracellular survivin on peripheral blood leukocytes (PBL). The binding of survivin to the surface of human PBL as well as the expression of adhesion molecules were assessed by FACS. The expression of adhesion molecules on leukocytes as a function of circulating survivin was analyzed in blood of 24 patients with RA and compared with eight healthy individuals. We show that extracellular survivin expresses immunomodulatory properties. It binds to the surface of the majority of granulocytes and a significant part of lymphocytes and monocytes inducing the activation of alpha-chains of beta-integrins and their ligand ICAM-1. Survivin-induced expression of alpha-chains of beta(2)-integrins is regulated by p38 MAPK and PI-3K but not by the NF-kappa B signaling pathway. Clinical relevance of our findings is supported by the in vivo association of high circulating survivin levels with an increased expression of CD11c on monocytes and granulocytes in RA patients. The results of our study demonstrate that extracellular survivin affects the phenotype of leukocytes having a possible impact on homing of inflammatory cells during arthritis.

  • 14.
    Narendra, Sudeep Chenna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
    Chalise, Jaya Prakash
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
    Höök, Nina
    Rheumatology and Inflammation Research, Sahlgrenska University Hospital, Göteborgs Universitet, Göteborg, Sweden.
    Magnusson, Mattias
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
    Dendritic cells activated by double-stranded RNA induce arthritis via autocrine type I IFN signaling.2014In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 95, no 4, p. 661-666Article in journal (Refereed)
    Abstract [en]

    Viral dsRNA can be found at the site of inflammation in RA patients, and intra-articular injection of dsRNA induces arthritis by activating type I IFN signaling in mice. Further, DCs, a major source of IFN-α, can be found in the synovium of RA patients. We therefore determined the occurrence of DCs in dsRNA-induced arthritis and their ability to induce arthritis. Here, we show, by immunohistochemistry, that cells expressing the pan-DC marker CD11c and the pDC marker 120G8 are present in the inflamed synovium in dsRNA-induced arthritis. Flt3L-generated and splenic DCs preactivated with dsRNA before intra-articular injection, but not mock-stimulated cells, clearly induced arthritis. Induction of arthritis was dependent on type I IFN signaling in the donor DCs, whereas IFNAR expression in the recipient was not required. Sorting of the Flt3L-DC population into cDCs (CD11c(+), PDCA-1(-)) and pDCs (CD11c(+), PDCA-1(+)) revealed that both subtypes were arthritogenic and produced type I IFN if treated with dsRNA. Taken together, these results demonstrate that viral nucleic acids can elicit arthritis by activating type I IFN signaling in DCs. Once triggered, autocrine type I IFN signaling in dsRNA-activated DCs is sufficient to propagate arthritis.

  • 15.
    Saeidi, Alireza
    et al.
    University of Malaya, Malaysia.
    Ellegård, Rada
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Yong, Yean K.
    University of Malaya, Malaysia.
    Tan, Hong Y.
    University of Malaya, Malaysia.
    Velu, Vijayakumar
    Emory University, GA 30322 USA.
    Ussher, James E.
    University of Otago, New Zealand.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Shankar, Esaki M.
    University of Malaya, Malaysia.
    Functional role of mucosal-associated invariant T cells in HIV infection2016In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 100, no 2, p. 305-314Article, review/survey (Refereed)
    Abstract [en]

    MAIT cells represent an evolutionarily conserved, MR1-restricted, innate-like cell subset that express high levels of CD161; have a canonical semi-invariant TCR iV alpha 7.2; and may have an important role in mucosal immunity against various bacterial and fungal pathogens. Mature MAIT cells are CD161(hi)PLZF(hi)IL-18R alpha(+)iV alpha 7.2(+)gamma delta-CD3(+)CD8(+) T cells and occur in the peripheral blood, liver, and mucosa of humans. MAIT cells are activated by a metabolic precursor of riboflavin synthesis presented by MR1 and, therefore, respond to many bacteria and some fungi. Despite their broad antibacterial properties, their functional role in persistent viral infections is poorly understood. Although there is an increasing line of evidence portraying the depletion of MAIT cells in HIV disease, the magnitude and the potential mechanisms underlying such depletion remain unclear. Recent studies suggest that MAIT cells are vulnerable to immune exhaustion as a consequence of HIV and hepatitis C virus infections and HIV/tuberculosis coinfections. HIV infection also appears to cause functional depletion of MAIT cells resulting from abnormal expression of T-bet and EOMES, and effective ART is unable to completely salvage functional MAIT cell loss. Depletion and exhaustion of peripheral MAIT cells may affect mucosal immunity and could increase susceptibility to opportunistic infections during HIV infection. Here, we review some of the important mechanisms associated with depletion and functional loss of MAIT cells and also suggest potential immunotherapeutic strategies to restore MAIT cell functions, including the use of IL-7 to restore effector functions in HIV disease.

  • 16.
    Smith, E
    et al.
    Lund University.
    Sigvardsson, Mikael
    Lund University.
    The roles of transcription factors in B lymphocyte commitment, development, and transformation2004In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 75, no 6, p. 973-981Article, review/survey (Refereed)
    Abstract [en]

    Studies of normal blood cell development and malignant transformation of hematopoietic cells have shown that the correctly regulated expression of stage- and lineage-specific genes is a key issue in hematopoiesis. Experiments in transgenic mice have defined a number of transcription factors such as SCL/Tal, core-binding factor/acute myeloid leukemia, and c-myb, all crucial for the establishment of definitive hematopoiesis and development of A blood cell lineages. Other regulators such as IKAROS, E47/E2A, early B cell factor, Sox-4, and B cell-specific activator protein (Pax-5) appear crucial, more or less selectively, for B lymphopoiesis, allowing for detailed analysis of the development of this lineage. In addition, several of these transcription factors are found translocated in human tumors, often resulting in aberrant gene expression or production of modified proteins. This article concerns the role of transcription factors in B lymphoid development with special focus on lineage initiation and commitment events but also to some extent on the roles of transcription factors in human B lymphoid malignancies.

  • 17.
    Tsapogas, P
    et al.
    Lund University.
    Breslin, T
    Lund University.
    Bilke, S
    Lund University.
    Lagergren, A
    Lund University.
    Månsson, R
    Lund University.
    Liberg, D
    Lund University.
    Peterson, C
    Lund University.
    Sigvardsson, Mikael
    Lund University.
    RNA analysis of B cell lines arrested at defined stages of differentiation allows for an approximation of gene expression patterns during B cell development2003In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 74, no 1, p. 102-110Article in journal (Refereed)
    Abstract [en]

    The development of a mature B lymphocyte from a bone marrow stem cell is a highly ordered process involving stages with defined features and gene expression patterns. To obtain a deeper understanding of the molecular genetics of this process, we have performed RNA expression analysis of a set of mouse B lineage cell fines representing defined stages of B cell development using Affymetrix(TM) microarrays. The cells were grouped based on their previously defined phenotypic features, and a gene expression pattern for each group of cell. lines was established. The data indicated that the cell lines representing a defined stage generally presented a high similarity in overall expression profiles. Numerous genes could be identified as expressed with a restricted pattern using dCHIP-based, quantitative comparisons or presence/absence-based, probabilistic state analysis. These experiments provide a model for gene expression during B cell development, and the correctly identified expression patterns of a number of control genes suggest that a series of cell fines can be useful tools in the elucidation of the molecular genetics of a complex differentiation process.

  • 18.
    Wilsson, Åsa
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Lundqvist, Helen
    Department of Medical Microbiology and Immunology, University of Göteborg.
    Gustafsson, Mikael
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Stendahl, Olle
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Killing of phagocytosed Staphylococcus aureus by human neutrophils requires intracellular free calcium1996In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 59, no 6, p. 902-907Article in journal (Refereed)
    Abstract [en]

    The mobilization of intracellular calcium plays an important role in regulating neutrophil activation. With this in mind we investigated the effect of intra- and extracellular calcium on the ability of human neutrophils to kill complement-opsonized Staphylococcus aureus. We found that a rise in intracellular calcium is necessary for efficient killing of phagocytosed S. aureus. In the presence of extracellular calcium, killing of ingested bacteria in calcium-buffered neutrophils compared with normal cells was slightly reduced. Calcium buffering had no effect on phagocytic uptake by the neutrophils, but did decrease the generation of toxic oxygen metabolites, measured as chemiluminescence (CL). In nondepleted and calcium-depleted cells, removal of extracellular calcium did not affect ingestion but did cause a marked decrease in the ability to kill the bacteria. In parallel, the CL response was substantially reduced or completely blocked. These data show that calcium is not a prerequisite for phagocytosis of S. aureus by human neutrophils, but does play a vital role in the post-ingestion killing of the bacteria by regulating the generation of toxic oxygen metabolites.

  • 19.
    Ydrenius, Liselotte
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Majeed, Meytham
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology.
    J Rasmusson, Birgitta
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology.
    Stendahl, Olle
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology.
    Särndahl, Eva
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Activation of cAMP-dependent protein kinase is necessary for actin rearrangements in human neutrophils during phagocytosis2000In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 67, no 4, p. 520-528Article in journal (Refereed)
    Abstract [en]

    We have investigated the role of cAMP and cAMP-dependent protein kinase (cAPK) in neutrophil phagocytosis. Inhibition of cAPK with H-89 reduced complement- and IgG-dependent phagocytosis to 83 and 46%, respectively. Fluorescence intensity measurements of phalloidin-stained actin in neutrophils showed a reduced amount of filamentous actin (F-actin) in pseudopods and around the phagosome in cells treated with H-89 or cAMP-elevating agents (forskolin and rolipram). The amount of phosphotyrosine-containing proteins was also reduced in pseudopods and around the phagosome. Taken together, the data show that cAMP/cAPK regulates F-actin reorganization during receptor-mediated phagocytosis, particularly triggered by IgG-FcR interaction. Our results support the hypothesis that active subcortical reorganization of F-actin is a prerequisite for FcR-mediated phagocytosis, but is less important during CR3-mediated ingestion.

  • 20.
    Zare, Fariba
    et al.
    University of Gothenburg, Sweden.
    Magnusson, Mattias
    University of Gothenburg, Sweden.
    Bergstrom, Tomas
    University of Gothenburg, Sweden.
    Brisslert, Mikael
    University of Gothenburg, Sweden.
    Josefsson, Elisabet
    University of Gothenburg, Sweden.
    Karlsson, Anna
    University of Gothenburg, Sweden.
    Tarkowski, Andrej
    University of Gothenburg, Sweden.
    Uric acid, a nucleic acid degradation product, down-regulates dsRNA-triggered arthritis2006In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 79, no 3, p. 482-488Article in journal (Refereed)
    Abstract [en]

    Uric acid, the naturally occurring degradation product of purine metabolism, is a danger signal, driving maturation of dendritic cells. It is well known that uric acid crystals display potent proinflammatory properties-the cause of gout-whereas the biological properties of soluble uric acid are less well documented. We have demonstrated previously that nucleic acids of endogenous and exogenons origin display proinflammatory properties. The aim of the present study was to assess the impact of soluble uric acid on in vivo inflammatory responses. Mice were administered with uric acid suspension in saline or saline alone prior to induction of nentrophil-mediated inflammation, delayed-type hypersensitivity, histamin-induced edema (measure of vasodilation capacity), as well as double-stranded (ds)RNA-triggered arthritis. Frequency and severity of arthritis were decreased significantly in mice exposed to dsRNA and simultaneously treated with uric acid as compared with salline-treated controls. Also, granulocyte-mediated inflammatory response and vasodilation capacity were reduced significantly in mice treated with uric acid as compared with their control group. The data suggest that down-regulation of inflammation was mediated by skewing the inflammatory response from the peripheral sites to the peritoneal cavity and down-regulating vasodilatatory capacity and thereby affecting leukocyte migration. In contrast, the T cell-mediated delayed-type hypersensitivity reaction was not affected significantly in mice exposed to uric acid. These findings demonstrate that uric acid displays a potent, distant anti-inflammatory effect in vivo. This property seems to be mediated by down-regulation of nentrophil influx to the site of inflammatory insult.

  • 21.
    Zare, Fariba
    et al.
    University of Gothenburg, Sweden .
    Magnusson, Mattias
    University of Gothenburg, Sweden .
    Nilsson Mollers, Linda
    University of Gothenburg, Sweden .
    Jin, Tao
    University of Gothenburg, Sweden .
    Tarkowski, Andrej
    University of Gothenburg, Sweden .
    Bokarewa, Maria
    University of Gothenburg, Sweden .
    Single-stranded polyinosinic acid oligonucleotides trigger leukocyte production of proteins belonging to fibrinolytic and coagulation cascades2008In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 84, no 3, p. 741-747Article in journal (Refereed)
    Abstract [en]

    The present study assessed the inductory effects of ds- and ssRNA on the leukocyte production of proteins belonging to fibrinolytic and coagulation cascades. Murine splenocytes were stimulated with dsRNA [polyinosinic: polycytidylic acid (polyIC)] and ssRNA sequences [polyinosinic acid (polyI), polycytidylic acid (polyC), and polyuridylic acid (polyU)]. The expression of plasminogen (Plg), tissue factor (TF), IL-6, and IFN-alpha was assessed. Intracellular tranduction mechanisms activated by oligonucleotides were evaluated using specific inhibitors of signaling pathways and genetically modified mice. polyIC efficiently and dose-dependently induced the expression of Plg, IL-6, and IFN-alpha, whereas TF was not induced by polyIC. polyI was unable to trigger IFN-alpha production, and it was efficiently inducing Plg and TF. IFN-alpha R and dsRNA-dependent protein kinase signaling were not required for the polyI-induced production of Plg or TF. Neither polyU nor polyC induced the expression of Plg or TF. Importantly, the presence of U- and C-nucleotide strands in the dsRNA significantly reduced expression of Plg and TF compared with polyI alone. Exposure of splenocytes to polyI activated the NF-kappa B pathway followed by the expression of TF and IL-6. In contrast, Plg production did not require NF-kappa B, was only partly down-regulated by p38 MAPK inhibitor, and was efficiently inhibited by insulin, indicating a different mechanism for its induction. ssRNA exerts its TF-generating properties through NF-kappa B activation in an IFN-alpha-independent manner. The expression of fibrinolytic versus coagulation proteins is regulated through distinctly different transduction pathways. As fibrinolytic and coagulation cascades are important components of inflammatory homeostatis, these findings might have importance for developement of new, targeted therapies.

1 - 21 of 21
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