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  • 101.
    Krusinska, Ewa
    et al.
    Dept of Mathemtics and iInformatics Paris.
    Babic, Ankica
    Linköping University, The Institute of Technology. Linköping University, Department of Biomedical Engineering, Medical Informatics.
    Mathiesen, Ulrik
    Oskarshamns hospital .
    Chowdhury, Shamsul
    Linköping University, The Institute of Technology. Linköping University, Department of Biomedical Engineering, Medical Informatics.
    Wigertz, Ove
    Linköping University, The Institute of Technology. Linköping University, Department of Biomedical Engineering, Medical Informatics.
    Bodemar, Göran
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Gastroenterology and Hepatology. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Franzén, Lennart
    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.
    A statistically rule-based decision support system for the management of patients with suspected liver disease1993In: Vol. 18, no 2, p. 113-130Article in journal (Refereed)
  • 102.
    Krusinska, Ewa
    et al.
    University of Wroclaw Poland.
    Babic, Ankica
    Linköping University, The Institute of Technology. Linköping University, Department of Biomedical Engineering, Medical Informatics.
    Mathiesen, Ulrik
    Oskarshamn Hospital .
    Franzén, Lennart
    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.
    Foberg, Ulla
    Dept of Infectious diseases Linköping.
    Frydén, Aril
    Linköping University, Department of Molecular and Clinical Medicine.
    Bodemar, Göran
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Gastroenterology and Hepatology. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Wigertz, Ove
    Linköping University, The Institute of Technology. Linköping University, Department of Biomedical Engineering, Medical Informatics.
    Empirical modelling versus commonly applied data analysis techniques as used for decision support in liver diseases1992In: MEDINFO92,1992, Amsterdam: Elsevier Science Publ , 1992, p. 949-Conference paper (Refereed)
  • 103.
    Kurz, Tino
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Gustafsson, Bertil
    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.
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Intralysosomal iron chelation protects against oxidative stress-induced cellular damage2006In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 273, no 13, p. 3106-3117Article in journal (Refereed)
    Abstract [en]

    Oxidant-induced cell damage may be initiated by peroxidative injury to lysosomal membranes, catalyzed by intralysosomal low mass iron that appears to comprise a major part of cellular redox-active iron. Resulting relocation of lytic enzymes and low mass iron would result in secondary harm to various cellular constituents. In an effort to further clarify this still controversial issue, we tested the protective effects of two potent iron chelators - the hydrophilic desferrioxamine (dfo) and the lipophilic salicylaldehyde isonicotinoyl hydrazone (sih), using cultured lysosome-rich macrophage-like J774 cells as targets. dfo slowly enters cells via endocytosis, while the lipophilic sih rapidly distributes throughout the cell. Following dfo treatment, long-term survival of cells cannot be investigated because dfo by itself, by remaining inside the lysosomal compartment, induces apoptosis that probably is due to iron starvation, while sih has no lasting toxic effects if the exposure time is limited. Following preincubation with 1 mm dfo for 3 h or 10 μm sih for a few minutes, both agents provided strong protection against an ensuing ∼LD50 oxidant challenge by preventing lysosomal rupture, ensuing loss of mitochondrial membrane potential, and apoptotic/necrotic cell death. It appears that once significant lysosomal rupture has occurred, the cell is irreversibly committed to death. The results lend strength to the concept that lysosomal membranes, normally exposed to redox-active iron in high concentrations, are initial targets of oxidant damage and support the idea that chelators selectively targeted to the lysosomal compartment may have therapeutic utility in diminishing oxidant-mediated cell injury. © 2006 The Authors.

  • 104.
    Kurz, Tino
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Leake, Alan
    von Zglinicki, Thomas
    Brunk, Ulf
    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.
    Lysosomal redox-active iron is important for oxidative stress-induced DNA damage2004In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1019, p. 285-288Article in journal (Refereed)
    Abstract [en]

    Data show that specifically chelating lysosomal redox-active iron can prevent most H2O2-induced DNA damage. Lysosomes seem to contain the major pool of redox-active labile iron within the cell. Under oxidative stress conditions, this iron may then relocate to the nucleus and play an important role for DNA damage by taking part in Fenton reactions.

  • 105.
    Kurz, Tino
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Leake, Alan
    von Zglinicki, Thomas
    Brunk, Ulf
    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.
    Relocalized redox-active lysosomal iron is an important mediator of oxidative-stress-induced DNA damage2004In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 378, no 3, p. 1039-1045Article in journal (Refereed)
    Abstract [en]

    Oxidative damage to nuclear DNA is known to involve site-specific Fenton-type chemistry catalysed by redox-active iron or copper in the immediate vicinity of DNA. However, the presence of transition metals in the nucleus has not been shown convincingly. Recently, it was proposed that a major part of the cellular pool of loose iron is confined within the acidic vacuolar compartment [Yu, Persson, Eaton and Brunk (2003) Free Radical Biol. Med. 34, 1243-1252, Persson, Yu, Tirosh, Eaton and Brunk (2003) Free Radical Biol. Med. 34, 1295-1305]. Consequently, rupture of secondary lysosomes, as well as subsequent relocation of labile iron to the nucleus, could be an important intermediary step in the generation of oxidative damage to DNA. To test this concept we employed the potent iron chelator DFO (desferrioxamine) conjugated with starch to form an HMM-DFO (high-molecular-mass DFO complex). The HMM-DFO complex will enter cells only via fluid-phase endocytosis and remain within the acidic vacuolar compartment, thereby chelating redox-active iron exclusively inside the endosomal/lysosomal compartment. Both free DFO and HMM-DFO equally protected lysosomal-membrane integrity against H2O 2-induced oxidative disruption. More importantly, both forms of DFO prevented H2O2-induced strand breaks in nuclear DNA, including telomeres. To exclude the possibility that lysosomal hydrolases, rather than iron, caused the observed DNA damage, limited lysosomal rupture was induced using the lysosomotropic detergent O-methyl-serine dodecylamine hydrochloride, subsequently, hardly any DNA damage was found. These observations suggest that rapid oxidative damage to cellular DNA is minimal in the absence of redox-active iron and that oxidant-mediated DNA damage, observed in normal cells, is mainly derived from intralysosomal iron translocated to the nucleus after lysosomal rupture.

  • 106.
    Kurz, Tino
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Terman, Alexei
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Geriatric .
    Gustafsson, Bertil
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    Lysosomes and oxidative stress in aging and apoptosis2008In: Biochimica et Biophysica Acta - General Subjects, ISSN 0304-4165, E-ISSN 1872-8006, Vol. 1780, no 11, p. 1291-1303Article in journal (Refereed)
    Abstract [en]

    The lysosomal compartment consists of numerous acidic vesicles (pH ~ 4-5) that constantly fuse and divide. It receives a large number of hydrolases from the trans-Golgi network, while their substrates arrive from both the cell's outside (heterophagy) and inside (autophagy). Many macromolecules under degradation inside lysosomes contain iron that, when released in labile form, makes lysosomes sensitive to oxidative stress. The magnitude of generated lysosomal destabilization determines if reparative autophagy, apoptosis, or necrosis will follow. Apart from being an essential turnover process, autophagy is also a mechanism for cells to repair inflicted damage, and to survive temporary starvation. The inevitable diffusion of hydrogen peroxide into iron-rich lysosomes causes the slow oxidative formation of lipofuscin in long-lived postmitotic cells, where it finally occupies a substantial part of the volume of the lysosomal compartment. This seems to result in a misdirection of lysosomal enzymes away from autophagosomes, resulting in depressed autophagy and the accumulation of malfunctioning mitochondria and proteins with consequent cellular dysfunction. This scenario might put aging into the category of autophagy disorders. © 2008 Elsevier B.V. All rights reserved.

  • 107.
    Kurz, Tino
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Terman, Alexei
    Linköping University, Department of Clinical and Experimental Medicine, Geriatric. Linköping University, Faculty of Health Sciences.
    Gustafsson, Bertil
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Brunk, Ulf T.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Lysosomes In Iron Metabolism, Ageing And Apoptosis2008In: Histochemistry and Cell Biology, ISSN 0948-6143, E-ISSN 1432-119X, Vol. 129, no 4, p. 389-406Article in journal (Refereed)
    Abstract [en]

    The lysosomal compartment is essential for a variety of cellular functions, including the normal turnover of most long-lived proteins and all organelles. The compartment consists of numerous acidic vesicles (pH ~4-5) that constantly fuse and divide. It receives a large number of hydrolases (~50) from the trans-Golgi network, and substrates from both the cells’ outside (heterophagy) and inside (autophagy). Many macromolecules contain iron that gives rise to an iron-rich environment in lysosomes that recently have degraded such macromolecules. Iron-rich lysosomes are sensitive to oxidative stress, while ‘resting’ lysosomes, which have not recently participated in autophagic events, are not. The magnitude of oxidative stress determines the degree of lysosomal destabilization and, consequently, whether arrested growth, reparative autophagy, apoptosis, or necrosis will follow. Heterophagy is the first step in the process by which immunocompetent cells modify antigens and produce antibodies, while exocytosis of lysosomal enzymes may promote tumor invasion, angiogenesis, and metastasis. Apart from being an essential turnover process, autophagy is also a mechanism by which cells will be able to sustain temporary starvation and rid themselves of intracellular organisms that have invaded, although some pathogens have evolved mechanisms to prevent their destruction. Mutated lysosomal enzymes are the underlying cause of a number of lysosomal storage diseases involving the accumulation of materials that would be the substrate for the corresponding hydrolases, were they not defective. The normal, low-level diffusion of hydrogen peroxide into iron-rich lysosomes causes the slow formation of lipofuscin in long-lived postmitotic cells, where it occupies a substantial part of the lysosomal compartment at the end of the life span. This seems to result in the diversion of newly produced lysosomal enzymes away from autophagosomes, leading to the accumulation of malfunctioning mitochondria and proteins with consequent cellular dysfunction. If autophagy were a perfect turnover process, postmitotic ageing and several age-related neurodegenerative diseases would, perhaps, not take place.

  • 108.
    Kågedal, Katarina
    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.
    Bironaite, D
    Öllinger, Karin
    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.
    Anthraquinone toxicity and apoptosis in primary cultures of rat hepatocytes.1999In: Free radical research, ISSN 1071-5762, E-ISSN 1029-2470, Vol. 31, p. 419-428Article in journal (Refereed)
  • 109.
    Leckström, A
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology.
    Lundquist, I
    Ma, Z
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology.
    Westermark, P
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Islet amyloid polypeptide and insulin relationship in a longitudinal study of the genetically obese (oblob) mouse. 1999In: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 18, p. 266-273Article in journal (Refereed)
  • 110.
    Li, Wei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences.
    Yuan, Ximing
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine.
    Ivanova, S.
    Laboratory of Biomedical Science, North Shore-LIE Research Institute, Manhasset, NY 11030, United States.
    Tracey, K.J.
    Laboratory of Biomedical Science, North Shore-LIE Research Institute, Manhasset, NY 11030, United States.
    Eaton, John Wallace
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    3-Aminopropanal, formed during cerebral ischaemia, is a potent lysosomotropic neurotoxin2003In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 371, no 2, p. 429-436Article in journal (Refereed)
    Abstract [en]

    Cytotoxic polyamine-derived amino aldehydes, formed during cerebral ischaemia, damage adjacent tissue (the so-called 'penumbra') not subject to the initial ischaemic insult. One such product is 3-aminopropanal (3-AP), a potent cytotoxin that accumulates in ischaemic brain, although the precise mechanisms responsible for its formation are still unclear. More relevant to the present investigations, the mechanisms by which such a small aldehydic compound might be cytotoxic are also not known, but we hypothesized that 3-AP, having the structure of a weak lysosomotropic base, might concentrate within lysosomes, making these organelles a probable focus of initial toxicity. Indeed, 3-AP leads to lysosomal rupture of D384 glioma cells, a process which clearly precedes caspase activation and apoptotic cell death. Immunohistochemistry reveals that 3-AP concentrates in the lysosomal compartment and prevention of this accumulation by the lysosomotropic base ammonia, NH3, protects against 3-AP cytotoxicity by increasing lysosomal pH. A thiol compound, N-(2-mercaptopropionyl)glycine, reacts with and neutralizes 3-AP and significantly inhibits cytoxocity. Both amino and aldehyde functions of 3-AP are necessary for toxicity: the amino group confers lysosomotropism and the aldehyde is important for additional, presently unknown, reactions. We conclude that 3-AP exerts its toxic effects by accumulating intralysosomally, causing rupture of these organelles and releasing lysosomal enzymes which initiate caspase activation and apoptosis (or necrosis if the lysosomal rupture is extensive). These results may have implications for the development of new therapeutics designed to lessen secondary damage arising from focal cerebral ischaemia.

  • 111. Liedberg, F
    et al.
    Andersson, H
    Bläckberg, M
    Chebil, G
    Davidsson, T
    Gudjonsson, S
    Jahnson, Staffan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Urology in Östergötland.
    Olsson, Hans
    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.
    Månsson, W
    Prospective study of transitional cell carcinoma in the prostatic urethra and prostate in the cystoprostatectomy specimen2007In: Scandinavian Journal of Urology and Nephrology, ISSN 0036-5599, E-ISSN 1651-2065, Vol. 41, no 4, p. 290-296Article in journal (Refereed)
    Abstract [en]

    Objectives. To prospectively evaluate the incidence of transitional cell carcinoma (TCC) in the prostatic urethra and prostate in the cystoprostatectomy specimen, investigate characteristics of bladder tumours in relation to the risk of involvement of the prostatic urethra and prostate and examine the sensitivity of preoperative loop biopsies from the prostatic urethra. Material and methods. Preoperatively, patients were investigated with cold cup biopsies from the bladder and transurethral loop biopsies from the bladder neck to the verumontanum. The prostate and bladder neck were submitted to sagittal whole-mount pathological analysis. Results. The incidence of TCC in the prostatic urethra and prostate in the cystoprostatectomy specimen was 29% (50/175 patients). Age, previous bacillus Calmette-Guérin treatment, carcinoma in situ (Cis) in the cold cup mapping biopsies and tumour grade were not associated with the risk of TCC in the prostatic urethra/prostate. Cis, multifocal Cis (≥2 locations) and tumour location in the trigone were significantly more common in cystectomy specimens with TCC in the prostatic urethra and prostate: 21/50 (42%) vs 32/125 (26%), p=0.045, 20/50 (40%) vs 27/125 (22%), p=0.023, and 20/50 (40%) vs 26/125 (21%), p=0.01, respectively. Preoperative resectional biopsies from the prostatic urethra in the 154 patients analysed identified 31/47 (66%) of patients with TCC in the prostatic urethra/prostate, with a specificity of 89%. The detection of stromal-invasive and non-stromal involvement was similar: 66% and 65%, respectively. Conclusions. The incidence of TCC in the prostatic urethra and prostate was 29% (50/175) in the cystoprostatectomy specimen. Preoperative biopsies from the prostatic urethra identified 66% of patients with such tumour growth. Our findings suggest that preoperative cold cup mapping biopsies of the bladder for detection of Cis add little extra information with regard to the risk of TCC in the prostatic urethra and prostate.

  • 112.
    Lundqvist, Helen
    et al.
    Department of Molecular and Clinical Medicine Linköping University.
    Dånmark, Staffan
    Department of Neuroscience and Locomotion Linköping University.
    Johansson, Uno
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology .
    Gustafsson, Håkan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Radiation Physics .
    Öllinger, Karin
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Evaluation of electron spin resonance for studies of superoxide anion production by human neutrophils interacting with Staphylococcus aureus and Staphylococcus epidermidis.2008In: Journal of Biochemical and Biophysical Methods, ISSN 0165-022X, E-ISSN 1872-857X, Vol. 70, no 6, p. 1059-1065Article in journal (Refereed)
    Abstract [en]

    The present study evaluates electron spin resonance (ESR) and the spin trapper 5-(diethoxyphosphoryl)-5-methyl-1-pyrroline-N-oxide (DEPMPO) for analysis of superoxide radical production by human neutrophils interacting with viable Staphylococcus aureus and Staphylococcus epidermidis bacteria. To avoid auto-activation due to interaction with glass surfaces, neutrophils were preincubated in plastic tubes until the peak response was reached, and then transferred to a quartz flat cell to record the ESR spectra. The time point for peak response was identified by parallel analysis of the bacteria-neutrophil interaction using luminol amplified chemiluminescence. We found detectable ESR spectra from neutrophils interacting with as few as five bacteria of the weak activating S. epidermidis per neutrophil. Addition of the NADPH oxidase inhibitor diphenylene iodonium totally abolished spectra. Catalase, DMSO or an iron chelator had no impact on the produced spectra and ionomycin, a selective activator of intracellular NADPH oxidase, gave significant ESR spectra. Taken together, our results indicate that DEPMPO is cell permeable and detects NADPH oxidase derived superoxide anions formed in phagosomes or released by human neutrophils phagocytosing viable S. aureus and S. epidermidis. The technique may be used as a sensitive tool to evaluate superoxide anion production in human neutrophils.

  • 113.
    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)
  • 114.
    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.
    Gustafsson, M.
    Dahlgren, C
    Dynamic Ca2+ changes in neutrophil phagosomes. A source for intracellular Ca2+ during phagolysosome formation?2000In: Cell Calcium, ISSN 0143-4160, E-ISSN 1532-1991, Vol. 27, no 6, p. 353-362Article in journal (Refereed)
    Abstract [en]

    An increase in cytosolic Ca2+ concentration periphagosomally is critical for phagolysosomal formation and neutrophil elimination of microbes. The Ca2+ increase could be achieved through release of Ca2+ from mobilized intracellular stores. Alternatively, Ca2+ that passively enter the phagosome during phagocytosis could be provided by the phagosome. Intraphagosomal Ca2+ changes in single human neutrophils was measured during phagocytosis of serum opsonized Fura-2-conjugated zymosan particles, using a digital image processing system for microspectrofluorometry. A decrease in phagosomal Ca2+ down to nanomolar concentrations was seen within minutes following phagosomal closure. Blockage of plasma membrane Ca2+ channels by econazole abolished this decrease. The fluorescence properties of Fura-2 zymosan were retained after phagocytosis and stable to pH changes, reactive oxygen species, and proteolytic enzymes. We suggest that Ca2+ ions present in the phagosome enter the cell cytosol through Ca2+ channels in the phagosomal membrane, achieving a localized Ca2+ rise that is important for phagosome processing.

  • 115. Marcusson-Ståhl, Maritha
    et al.
    Cederbrant, Karin
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    A flow-cytometric NK-cytotoxicity assay adapted for use in rat repeated dose toxicity studies.2003In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 193, p. 269-279Article in journal (Refereed)
  • 116.
    Martinsson, Klara
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. 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.
    Lack of Fcγ-receptors increases circulating immune complexes but delays development of tissue immune complex depositsManuscript (preprint) (Other academic)
    Abstract [en]

    Inorganic mercury (Hg) induces in susceptible mouse strains a T-cell dependent, systemic autoimmune condition (HgIA) characterized by immunostimulation, antinuclear antibodies, and immune-complex (IC) deposits in glomeruli and vessel walls. Activating Fcγ-receptors (FcγRs) are important for induction of HgIA. We have examined if activating FcγRs affect circulating immune complexes (CIC), the initial development of tissue IC deposits and their composition in HgIA. BALB/c mice with a targeted mutation for activating FcγRs and BALB/c mice without any mutation (wild type - wt - mice) were treated up to 35 days with Hg. Wild type mice showed a significant but modest increase of CIC from day 12 until day 18 and day 35 for IgG2a- and IgG1-containing CIC, respectively. Mercury-treated FcγR−/− mice showed significantly higher CIC levels than Hg-treated wt mice during the entire treatment time for IgG1-CIC, and after 26 and 35 days for IgG2a-CIC. Tissue IC deposits developed later in the FcγR−/− mice especially in the renal mesangium. After 35 days of Hg treatment the fraction of mice with and/or the amount of IgG1 and C3c deposits were significantly reduced in vessel walls and for IgG1 also in the renal mesangium compared with wt mice. We conclude that susceptible mice lacking activating FcγRs respond to an autoimmune stimulus with increased levels and altered quality of CIC compared with wt mice. It is likely that lack of FcγRs reduced elimination of CIC as indicated by delayed and significantly reduced IC deposits in the tissues of mice without activating receptors.

  • 117.
    Martinsson, Klara
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. 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.
    The role of Fc-receptors in murine mercury-induced systemic autoimmunity2006In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 144, no 2, p. 309-318Article in journal (Refereed)
    Abstract [en]

    Inorganic mercury (Hg) in genetically susceptible mouse strains induces a T cell-dependent, systemic autoimmune condition (HgIA) characterized by immunostimulation, anti-nuclear antibodies (ANA) and systemic immune-complex (IC) deposits. The exact phenotypic expression of HgIA in different strains depends on H-2 and non-H-2 genes. Fc receptors (FcRs) are important in the development of many autoimmune diseases. In this study, the effect of targeted mutations for activating and inhibiting FcRs in the BALB/c model of HgIA was examined. Hg-treated BALB/c mice without mutation (wild-type, wt) showed heavy IC deposits in the renal glomerular mesangium, as well as in renal and splenic vessel walls. The renal mesangial IC deposits were severely reduced in Hg-treated BALB/c mice without the gamma-chain (lack of the activating receptors FcgammaRI, FcgammaRIII and FcinRI), but unchanged in mice lacking the inhibitory FcgammaRIIB. The Hg-induced vessel wall IC deposits present in wt mice were abolished and reduced in the FcRgamma and FcgammaRIIB strains, respectively. Hg-treated BALB/c wt mice and mice without the gamma-chain showed an increase in serum IgE, while the increase in IgG1 was attenuated in the latter strain. In contrast, absence of the inhibiting FcgammaRIIB augmented the Hg-induced increase of both serum IgG1 and IgE. In conclusion, FcRs are important mainly for the induction of systmeic IC deposits in the HgIA model, but also affects serum IgG1 and IgE levels.

  • 118.
    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.

  • 119.
    Mathiesen, Ulrik
    et al.
    Oskarshamn Hospital .
    Krusinska, Ewa
    Technical University of Wroclaw, Poland .
    Bodemar, Göran
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Gastroenterology and Hepatology. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Chowdhury, Shamsul
    Linköping University, The Institute of Technology. Linköping University, Department of Biomedical Engineering, Medical Informatics.
    Babic, Ankica
    Linköping University, The Institute of Technology. Linköping University, Department of Biomedical Engineering, Medical Informatics.
    Franzén, Lennart
    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.
    Frydén, Aril
    Linköping University, Department of Molecular and Clinical Medicine.
    Wigertz, Ove
    Linköping University, The Institute of Technology. Linköping University, Department of Biomedical Engineering, Medical Informatics.
    Investigation and follow-up of patients with raised levels of liver transaminases. Computerised support for high quality and cost-effetiveness1994In: Medical Informatics in Europe MIE94,1994, 1994, p. 196-Conference paper (Refereed)
  • 120. McAdam, KPWJ
    et al.
    Raynes, JG
    Alpers, MP
    Westermark, Gunilla
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Westermark, P
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Amyloidosis: a global problem common in Papua New Guinea. 1999In: Papau New Guinea Medical Journal, ISSN 0031-1480, Vol. 39, p. 284-296Article in journal (Refereed)
  • 121. Mellergård, Johan
    et al.
    Havarinasab, Said
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology.
    Hultman, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Short- and long-term effects of T-cell modulating agents in experimental autoimmunity2004In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 196, no 3, p. 197-209Article in journal (Refereed)
    Abstract [en]

    Due to the easy and reliable induction of a disease condition with many of the features present in human autoimmunity, mercury-induced autoimmunity (mHgAI) in rodents is a favourable autoimmune model. Genetically susceptible (H-2 s) mice develop in response to mercury (Hg) a systemic autoimmune condition with antinucleolar antibodies (ANoA) targeting the protein fibrillarin, transient polyclonal B-cell activation, hyperimmunoglobulinemia, and systemic immune-complex (IC) deposits. In order to study the short- and long-term effects of treatment with immunomodulating agents on the disease parameters in HgAI, groups of B10.S (H-2s) mice were given 6mg HgCl2/l drinking water for 22 weeks. Three weeks initial treatment with cyclosporin A (CyA), a high dose of tacrolimus (HD tacrolimus), or anti-CD4 monoclonal antibody (a-CD4) inhibited induction of ANoA and IC deposit by Hg. This effect persisted for the subsequent 19 weeks when the mice were only treated with Hg. Initial treatment with anti-IL-4 monoclonal antibody (a-IL-4) for 3 weeks inhibited induction of IgE and IC deposits by Hg, but not ANoA. However, subsequent treatment with Hg without a-IL-4 for 19 weeks induced IC deposits. The T-cell modulating agents aggravated some of the HgAI disease parameters: a-CD4 stimulated the polyclonal B-cell activation, a-IL-4 increased the IgG antichromatin antibody response, and a low dose of tacrolimus (LD tacrolimus) enhanced the ANoA, the polyclonal B-cell activation, and the IC deposits. We conclude that a short initial treatment with a-CD4 or CyA efficiently protects against induction of systemic autoimmunity for an extended period of time. However, some of the T-cell modulating agents, especially a low dose of tacrolimus, aggravate autoimmune manifestations not only during ongoing treatment, but also after treatment with these agents has ceased.

  • 122.
    Myhrinder, Anna Lanemo
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Hellqvist, Eva
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Jansson, Mattias
    Department of Genetics and Pathology, Uppsala University, SE-781 85 Uppsala, Sweden.
    Nilsson, Kenneth
    Department of Genetics and Pathology, Uppsala University, SE-781 85 Uppsala, Sweden.
    Hultman, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Jonasson, Jon
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Rosenquist, Richard
    Department of Genetics and Pathology, Uppsala University, SE-781 85 Uppsala, Sweden.
    Rosén, Anders
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Molecular characterization of neoplastic and normal "sister" lymphoblastoid B-cell lines from chronic lymphocytic leukemia2013In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 54, no 8, p. 1769-1779Article in journal (Refereed)
    Abstract [en]

    Chronic lymphocytic leukemia (CLL) B-cells resemble self-renewing CD5 + B-cells carrying auto/xeno-antigen-reactive B-cell receptors (BCRs) and multiple innate pattern-recognition receptors, such as Toll-like receptors and scavenger receptors. Integration of signals from BCRs with multiple surface membrane receptors determines whether the cells will be proliferating, anergic or apoptotic. To better understand the role of antigen in leukemogenesis, CLL cell lines producing monoclonal antibodies (mAbs) will facilitate structural analysis of antigens and supply DNA for genetic studies. We present here a comprehensive genotypic and phenotypic characterization of available CLL and normal B-cell-derived lymphoblastoid cell lines (LCLs) from the same individuals (n = 17). Authenticity and verification studies of CLL-patient origin were done by IGHV sequencing, fluorescence in situ hybridization (FISH) and DNA/short tandem repeat (STR) fingerprinting. Innate B-cell features, i.e. natural Ab production and CD5 receptors, were present in most CLL cell lines, but in none of the normal LCLs. This panel of immortalized CLL-derived cell lines is a valuable reference representing a renewable source of authentic Abs and DNA.

  • 123. Neuzil, J.
    et al.
    Svensson, Irene
    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.
    Weber, T.
    Weber, C.
    Brunk, Ulf
    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.
    Alfa-Tocopheryl-induced apoptosis in Jurkat T cells involves caspase-3 activation, and both mitochondrial and lysosomal destabilization.1999In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 445, p. 295-300Article in journal (Refereed)
  • 124.
    Neuzil, Jiri
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Kågedal, Katarina
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Andrea, L
    Weber, Christian
    Brunk, Ulf
    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.
    Vitamin E analogs: A new class of multiple action agents with anti-neoplastic and anti-atherogenic activity2002In: Apoptosis (London), ISSN 1360-8185, E-ISSN 1573-675X, Vol. 7, no 2, p. 179-187Article in journal (Refereed)
    Abstract [en]

    The incidence of cancer and atherosclerosis, two most common causes of death in developed countries, has been stagnating or, even, increasing. Drugs effective against such conditions are needed and, in this regard, the potential anti-atherosclerotic activity of vitamin E analogs has been studied extensively. Surprisingly, recent results indicate that these agents may also exert anti-neoplastic effects. Here we review the evidence that particular analogs of vitamin E may act as both anti-atherogenic and anti-cancer agents, and discuss the possible molecular bases for these actions.

  • 125.
    Neuzil, Jiri
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Weber, Tobias
    Terman, Alexei
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Weber, Christian
    Brunk, Ulf
    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.
    Vitamin E analogues as inducers of apoptosis: implications for their potential anti-neoplastic role2001In: Redox report, ISSN 1351-0002, E-ISSN 1743-2928, Vol. 6, p. 143-151Article in journal (Refereed)
  • 126.
    Neuzil, Jiri
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Zhao, Ming
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Ostermann, Georg
    Sticha, Martin
    Gellert, Nina
    Weber, Christian
    Eaton, John Wallace
    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.
    Brunk, Ulf
    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.
    Alfa-Tocopheryl succinate, an agent with in vivo anti-tumour activity, induces apoptosis by causing lysosomal instability2002In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 362, p. 709-715Article in journal (Refereed)
  • 127. Nielsen, J.B
    et al.
    Ekstrand, Jimmy
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology.
    Zalups, R.K
    Söderkvist, Peter
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology.
    Hultman, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Inheritance of susceptibility: mercury kinetics in two mouse strains (A.SW and B10.S) and their F1 generation.2006In: Metal ions in biological systems, ISSN 0161-5149, E-ISSN 2154-9214, Vol. 9, p. 351-355Article in journal (Refereed)
    Abstract [en]

       

  • 128. Nielsen, JB
    et al.
    Hultman, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Experimental studies on genetically determined susceptibility to mercury-induced autoimmune response. 1999In: Renal failure, ISSN 0886-022X, E-ISSN 1525-6049, Vol. 21, p. 343-348Article in journal (Refereed)
  • 129.
    Nielsen, JB
    et al.
    Univ So Denmark, DK-5000 Odense C, Denmark Linkoping Univ, Linkoping, Sweden.
    Hultman, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Mercury-induced autoimmunity in mice2002In: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 110, p. 877-881Article in journal (Refereed)
    Abstract [en]

    We have studied the effect of gender, genetics, and toxicokinetics on immune parameters in mercury-induced autoimmunity in mice. Data strongly suggest that the mechanism for mercury-induced autoimmunity involves modification of the autoantigen fibrillarin by mercury followed by a T-cell-dependent immune response driven by the modified fibrillarin. Mice with different H-2 haplotypes were treated with (HgCl2)-Hg-203 in a dose of 0.5-16 mg Hg/L drinking water for 10 weeks. Whole-body accumulation and renal accumulation of mercury were assessed. Serum antinuclear antibodies were used to evaluate the autoimmune response, and serum immunoglobulin E (IgE) to study effects on T-helper cells of type 2. Strains with a susceptible H-2 haplotype developed autoantibodies to the nucleolar protein fibrillarin (AFA) in a dose-dependent pattern within 2 weeks. The substantially lower whole-body and organ mercury level needed to induce AFA in the susceptible A.SW strain compared with the H-2 congenic B10.S strain demonstrates that genetic factors outside the H-2 region modify the autoimmune response. Mouse strains without the susceptible haplotype did not develop any autoimmune reaction irrespective of dose and organ deposition of mercury. In susceptible mouse strains, males and females had different thresholds for induction of autoimmune reactions. In susceptible strains, serum IgE increased dose dependently and reached a maximum after 1-2.5 weeks. A susceptible H-2 haplotype is therefore a prerequisite for the autoimmune response. Mercury exposure will modulate the response, qualitatively through the existence of dose-related thresholds for autoimmune response and quantitatively as increasing doses cause increasing autoimmune response. Further, gender and non-H-2 genes modulate both the induction and subsequent development of AFA. Induction of IgE seems not to be mechanistically linked to the AFA response.

  • 130.
    Nilsson, Cathrine
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Linköping University, Faculty of Health Sciences.
    Kågedal, Katarina
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Linköping University, Faculty of Health Sciences.
    Johansson, Uno
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Linköping University, Faculty of Health Sciences.
    Öllinger, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Analysis of cytosolic and lysosomal pH in apoptotic cells by flow cytometry2004In: Methods in Cell Science, ISSN 1381-5741, Vol. 25, no 3-4, p. 185-194Article in journal (Refereed)
    Abstract [en]

    Several reports indicate that the cytosol is acidified during apoptosis although the mechanism is not yet fully elucidated. The most acidic organelle found in the cell is the lysosome, raising the possibility that lysosomal proton release may contribute to the cytosolic acidification. We here describe methods for measurement of the cytosolic and lysosomal pH in U937 cells by a dual-emission ratiometric technique suitable for flow cytometry. Cytosolic pH was analysed in cells loaded with the fluorescent probe BCECF, while lysosomal pH was determined after endocytosis of FITC-dextran. Standard curves were obtained by incubating cells in buffers with different pH in the presence of the proton ionophore nigericin. Apoptosis was induced by exposure of cells to 10ng/ml TNF- for 4h, and apoptotic cells were identified using a fluorescent marker for active caspases. By gating of control and apoptotic cells, the cytosolic and lysosomal pH were calculated in each population. The cytosolic pH was found to decrease from 7.2 ± 0.1 to 5.8s±0.1 and the lysosomal increased from 4.3±0.4 to 5.2±0.3. These methods will be useful in future attempts to evaluate the involvement of lysosomes in the acidification of the cytosol during apoptosis.

  • 131.
    Nilsson, Cathrine
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Roberg, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Oto-Rhiono-Laryngology and Head & Neck Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Reconstruction Centre, Department of ENT - Head and Neck Surgery UHL.
    Grafström, Roland C.
    Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden.
    Öllinger, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Intrinsic differences in cisplatin sensitivity of head and neck cancer celllines correlates to lysosomal pH2010In: Head and Neck, ISSN 1043-3074, E-ISSN 1097-0347, Vol. 32, no 9, p. 1185-1194Article in journal (Refereed)
    Abstract [en]

    Cisplatin is part of the treatment regime of head and neck squamous cell carcinomas (HNSCC). In order to predict the clinical outcome of the treatment, markers for evaluation of the intrinsic cisplatin sensitivity are inquired. In this study we characterize the lysosomal compartment and compare cisplatin sensitivity in five HNSCC lines and normal oral keratinocytes (NOKs). Cisplatin sensitivity differed 3-fold between the least and most sensitive cell lines, and the cisplatin LD50 correlated significantly to lysosomal pH, which varied from 4.3 in NOKs to 4.9 in the most resistant HNSCC line. Lysosomes are acidified by the V0V1-ATPase complex located in the lysosomal membrane. Interestingly, in cell lines exhibiting high lysosomal pH, we found decreased expression of the V0V1-ATPase B2 subunit, possibly explaining the defective acidification. In all cell lines, exposure to cisplatin caused activation of caspase-3. Cisplatin exposure was accompanied by lysosomal membrane permeabilization and inhibition of the llysosomal cathepsins B, D and L partly prevented cell death. No correlation between cisplatin sensitivity and expression of cathepsins B, D and L or secretion of their respective proforms into the culture medium was found in the cell lines studied. We conclude that lysosomal pH and expression of V0V1-ATPase subunits are possible future markers of intrinsic cisplatin sensitivity.

  • 132.
    Norberg, U.
    et al.
    Dept. of Transplant. and Liver Surg., Sahlgrenska Universitetssjukhuset, Gothenburg, Sweden.
    Soderlind, K.
    Franzén, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Loven, C.
    Strandelius, E.
    Wolfbrandt, A.
    Backman, L.
    A modified 'Spanish model' for organ donation in the southeast region of Sweden2000In: Transplantation Proceedings, ISSN 0041-1345, E-ISSN 1873-2623, Vol. 32, no 1, p. 72-74Conference paper (Other academic)
    Abstract [en]

    [No abstract available]

  • 133. Nowak, G
    et al.
    Westermark, P
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Wernerson, A
    Herlenius, G
    Sletten, K
    Ericzon, BG
    Liver transplantation as rescue treatment in a patient with primary AL kappa.2000In: Transplant International, ISSN 0934-0874, E-ISSN 1432-2277, Vol. 13, p. 92-97Article in journal (Refereed)
  • 134.
    Olejnicka, Beata
    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.
    Andersson, A.
    Tyrberg, B.
    Dalen, H.
    Brunk, Ulf
    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.
    Beta cells, oxidative stress, lysosomal stability and apoptotic/neurotic cell death.1999In: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 1, p. 305-315Article in journal (Refereed)
  • 135.
    Olejnicka, Beata
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pulmonary Medicine. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Respiratory Medicine UHL.
    Dalen, H.
    Brunk, Ulf
    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.
    Minute oxidative stress is sufficient to induce apoptotic death of NTT insulinoma cells.1999In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 107, p. 747-761Article in journal (Refereed)
  • 136.
    Olsen, KE
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Sletten, K
    Sandgren, O
    Olsson, H
    Myrvold, K
    Westermark, P
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    What is the role of giant cells in AL-amyloidosis?1999In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 6, p. 89-97Article in journal (Refereed)
  • 137.
    Olsen, KE
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Sletten, K
    Westermark, P
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    The use of subcutaneous fat tissue for amyloid typing by enzyme-linked immunosorbent assay.1999In: American Journal of Clinical Pathology, ISSN 0002-9173, E-ISSN 1943-7722, Vol. 111, p. 355-362Article in journal (Refereed)
  • 138.
    Olsson, Hans
    et al.
    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.
    Jahnson, Staffan
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Urology in Östergötland.
    SUB STAGING OF T1 BLADDER TUMOURS2009In: in EUROPEAN UROLOGY SUPPLEMENTS, vol 8, issue 4, 2009, Vol. 8, no 4, p. 287-287Conference paper (Refereed)
    Abstract [en]

    n/a

  • 139.
    Palfi, Miodrag
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Transfusion Medicine. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Immunology and Transfusion Medicine.
    Gunnarsson, Cecilia
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    The frequency of anti-C + anti-G in the absence of anti-D in alloimmunized pregnancies2001In: Transfusion Medicine, ISSN 0958-7578, E-ISSN 1365-3148, Vol. 11, no 3, p. 207-210Article in journal (Refereed)
    Abstract [en]

    Anti-D+C are often initially identified in sera from alloimmunized women. Anti-G may be present in these samples, mimicking anti-D+C, and therefore the differentiation of anti-D, -C and -G may be important. Sera from 27 alloimmunized women, initially identified as containing anti-D + anti-C, were analysed by adsorption/elution studies in the presence of polyethylene glycol (PEG) using R0r (D+C-G+) and r'r(D-C+G+) red blood cells (RBC). Additionally, 15/27 samples were tested by adsorption in the presence of PEG and subsequently warm elution, using rGr (D-C-G+) RBC. Anti-G + anti-C, without anti-D, were identified in 4/27 samples (14.8%) and none of the newborn children needed postpartum treatment. The combination of D+G, D+C and D+C+G antibodies occurred in 25.9%, 11.1% and 48.1% of the women, respectively. Overall, anti-G was detected in 24/27 samples (88.9%). Pregnant women shown to have anti-G+C but not anti-D should receive Rh immune globulin. Additionally, the finding of apparent anti-D+C during pregnancy in D-negative spouses may lead to paternity testing and therefore a correct antibody identification is necessary.

  • 140. Peng, Siwei
    et al.
    Westermark, Gunilla
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Näslund, Jan
    Häggqvist, Bo
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Glennert, Johanna
    Westermark, Per
    Medin and medin-amyloid in ageing inflamed and non-inflamed temporal arteries2002In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 196, p. 91-96Article in journal (Refereed)
  • 141.
    Persson, H.Lennart
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Respiratory Medicine.
    Kurz, Tino
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    Eaton, John Wallace
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    Radiation-induced cell death: Importance of lysosomal destabilization2005In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 389, no 3, p. 877-884Article in journal (Refereed)
    Abstract [en]

    The mechanisms involved in radiation-induced cellular injury and death remain incompletely understood. In addition to the direct formation of highly reactive hydroxyl radicals (HO.) by radiolysis of water, oxidative stress events in the cytoplasm due to formation of H2O2 may also be important. Since the major pool of low-mass redox-active intracellular iron seems to reside within lysosomes, arising from the continuous intralysosomal autophagocytotic degradation of ferruginous materials, formation of H2O2 inside and outside these organelles may cause lysosomal labilization with release to the cytosol of lytic enzymes and low-mass iron. If of limited magnitude, such release may induce 'reparative autophagocytosis', causing additional accumulation of redox-active iron within the lysosomal compartment. We have used radio-resistant histiocytic lymphoma (J774) cells to assess the importance of intralysosomal iron and lysosomal rupture in radiation-induced cellular injury. We found that a 40 Gy radiation dose increased the 'loose' iron content of the (still viable) cells approx. 5-fold when assayed 24 h later. Cytochemical staining revealed that most redox-active iron was within the lysosomes. The increase of intralysosomal iron was associated with 'reparative autophagocytosis', and sensitized cells to Iysosomal rupture and consequent apoptotic/necrotic death following a second, much lower dose of radiation (20 Gy) 24 h after the first one. A high-molecular-mass derivative of desferrioxamine, which specifically localizes intralysosomally following endocytic uptake, added to the culture medium before either the first or the second dose of radiation, stabilized lysosomes and largely prevented cell death. These observations may provide a biological rationale for fractionated radiation. © 2005 Biochemical Society.

  • 142. Pollard, K Michael
    et al.
    Arnush, Marc
    Hultman, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Kono, Dwight H
    Costimulation requirements of induced murine systemic autoimmune disease2004In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 173, no 9, p. 5880-5887Article in journal (Refereed)
    Abstract [en]

    Costimulation between T cells and APC is required for productive immune responses. A number of receptor/ligand pairs have been shown to mediate costimulation, including CD28/B7 molecules (CD80 and CD86), CD40/CD40 ligaad (CD40L, CD154), and LFA-1 (CD18)/ICAM-1 (CD54). T-B cell Costimulation also plays a significant role in autoimmune diseases such as systemic lupus erythematosus. Murine HgCl2-induced autoimmunity (mHgIA) is a T cell-dependent systemic autoimmune disease that shares a number of common pathogenic mechanisms with idiopathic lupus. In this report, the significance of costimulation in mHgIA is examined by attempting to induce disease in mice deficient in either CD40L, CD28, or ICAM-1. Unlike absence of ICAM-1, homozygous deficiencies in either CD40L or CD28 significantly reduced the development of mHgIA. CD40L displayed a gene dosage effect as heterozygous mice also showed reduction of autoantibody responses and immunopathology. Markers of T cell activation such as CD44 and CTLA-4 were associated with disease expression in wild-type and ICAM-1-deficient mice but not in CD40L- or CD28-deficient mice. Absence of CTLA-4 expression in CD40L-/- mice suggests that signaling via both CD28 and CD40L is important for T cell activation and subsequent autoimmunity in mHgIA. Attempts to circumvent the absence of CD40L by increasing CD28 signaling via agonistic Ab failed to elicit CTLA-4 expression. These findings indicate that breaking of self-tolerance in mHgIA requires signaling via both the CD28/B7 and CD40/CD40L pathways.

  • 143. Pollard, K Michael
    et al.
    Hultman, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Fibrillarin autoantibodies2007In: Autoantibodies / [ed] Shoenfeld, Yehuda,Gershwin, M. Eric och Meroni, Pier-Luigi, Elsevier Science , 2007, p. 317-323Chapter in book (Other academic)
  • 144.
    Pollard, K. Michael
    et al.
    The Scripps Research Institute, La Jolla, CA, USA.
    Hultman, Per
    Linköping University, Department of Molecular and Clinical 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.
    Skin-lightening creams are a possible exposure risk for systemic lupus erythemato sus: comment on the article by Finckh et al.2007In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 56, no 5, p. 1721-1721Article in journal (Other academic)
    Abstract [en]

      

  • 145.
    Pollard, K Michael
    et al.
    USA .
    Hultman, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Kono, Dwight H
    USA .
    Immunology and genetics of induced systemic autoimmunity2005In: Autoimmunity Reviews, ISSN 1568-9972, E-ISSN 1873-0183, Vol. 4, no 5, p. 282-288Article in journal (Refereed)
    Abstract [en]

    Systemic lupus erythematosus is a multigenic disorder of unknown etiology. To investigate the role of specific genes in lupus, we have examined the effects of single gene deletions on mercury-induced autoimmunity. Deficiency of certain genes abrogated induction of autoimmunity, while absence of others had little effect. The most interesting observations were obtained with genes related to interferon-γ. Genes involved in upregulation of IFN-γ expression did not significantly influence autoimmunity whereas absence of IFN-γ or IFN-γ receptor led to greatly reduced autoantibody responses and immunopathology. Absence of IRF-1, a gene expressed in response to IFN-γ, resulted in selective retention of anti-chromatin autoantibodies demonstrating that specific defects in signaling pathways and gene expression subsequent to IFN-γ/IFN-γ receptor interaction influence specific disease parameters. These studies show that single gene deletions can have various outcomes ranging from no effect, suppression of one or more features of disease, to suppression of all features of disease, and that all three outcomes can be observed in the IFN-γ pathway. IFN-γ influences the expression and function of other lupus relevant genes such as IL-6 and β2microglobulin, therefore the effects of these gene deletions on disease expression may also reflect responses downstream of IFN-γ function. © 2005 Elsevier B.V. All rights reserved.

  • 146.
    Pollard, K Michael
    et al.
    Scripps Research Institute.
    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.
    Kono, Dwight H
    Scripps Research Institute.
    Toxicology of Autoimmune Diseases2010In: CHEMICAL RESEARCH IN TOXICOLOGY, ISSN 0893-228X, Vol. 23, no 3, p. 455-466Article in journal (Refereed)
    Abstract [en]

    Susceptibility to most autoimmune diseases is dependent on polygenic inheritance, environmental factors, and poorly defined stochastic events. One of the significant challenges facing autoimmune disease research is in identifying the specific events that trigger loss of tolerance and autoimmunity. Although many intrinsic factors, including age, sex, and genetics, contribute to autoimmunity, extrinsic factors such as drugs, chemicals, microbes, or other environmental factors can also act as important initiators. This review explores how certain extrinsic factors, namely, drugs and chemicals, can promote the development of autoimmunity, focusing oil a few better characterized agents that, in most instances, have been shown to produce autoimmune manifestations in human populations. Mechanisms of autoimmune disease induction are discussed in terms of research obtained using specific animal models. Although a number of different pathways have been delineated for drug/chemical-induced autoimmunity, some similarities do exist, and a working model is proposed.

  • 147. Pollard, K Michael
    et al.
    Hultman, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Kono, Dwight H
    Using single-gene deletions to identify checkpoints in the progression of systemic autoimmunity2003In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 987, p. 236-239Article in journal (Refereed)
    Abstract [en]

    Systemic lupus erythematosus is a multigenic disorder of unknown etiology. To investigate the roles that specific genes play in lupus, we have examined the disease profiles in mice with single-gene deletions. In total, some 17 genes have been studied. Absence of certain genes, such as CD40L, CD28, or Igh6, abrogated induction of autoimmunity. Other genes, such as Igh5, IL-4, or ICAM-1, had little effect on the development of disease. Intermediate effects were observed in IL-6-deficient mice, while absence of β2-microglobulin resulted in loss of hypergammaglobulinemia and IgG1 autoantibodies, but produced little change in anti-chromatin antibodies or glomerular deposits. The most interesting observations were obtained with genes related to the expression or function of interferon-γ (IFN-γ). Reductions in IFN-γ levels in murine lupus are associated with reductions in both autoantibody levels and immune-complex- mediated pathology. Genes involved in up-regulation of IFN-γ expression, such as IL-12, STAT-4, or ICE, did not significantly influence autoimmunity, whereas absence of IFN-γ or IFN-γ receptor led to greatly reduced autoantibody response and immunopathology. Absence of IRF-1, a gene ex-pressed in response to IFN-γ, resulted in selective retention of anti-chromatin antibodies but little glomerular pathology. These studies suggest that the presence of a baseline level of IFN-γ, rather than increased expression, is important for autoimmunity. Furthermore, as the IRF-1 knockout demonstrates, specific defects in signaling pathways and gene expression subsequent to IFN-γ/IFN-γ receptor interaction may influence only certain disease parameters. It has not escaped our attention that IFN-γ influences the expression and function of other immunologically relevant genes, such as IL-4, IL-6, and β2-microglobulin. Thus, these genes may be part of the downstream events following IFN-γ/IFN-γ receptor interaction that promote the development of autoimmunity.

  • 148. Pollard, KM
    et al.
    Pearson, DL
    Hultman, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Deane, TN
    Lindh, U
    Kono, DH
    Xenobiotic acceleration of idiopathic systemic autoimmunity in lupus-prone BXSB mice.2001In: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 109, p. 27-33Article in journal (Refereed)
  • 149. Pollard, KM
    et al.
    Pearson, DL
    Hultman, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Hildebrandt, B
    Kono, DH
    Lupus-prone mice as models to study xenobiotic-induced acceleration of systemic autoimmunity. 1999In: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 107, p. 729-735Article in journal (Refereed)
  • 150. Quinn, Carmel M.
    et al.
    Kågedal, Katarina
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Terman, Alexei
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Stroikin, Yuri
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Brunk, Ulf
    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.
    Jessup, Wendy
    Garner, B
    Induction of fibroblast apolipoprotein E expression during apoptosis, starvation-induced growth arrest and mitosis2004In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 378, no 3, p. 753-761Article in journal (Refereed)
    Abstract [en]

    Apolipoprotein E (apoE) mediates the hepatic clearance of plasma lipoproteins, facilitates cholesterol efflux from macrophages and aids neuronal lipid transport. ApoE is expressed at high levels in hepatocytes, macrophages and astrocytes. In the present study, we identify nuclear and cytosolic pools of apoE in human fibroblasts. Fibroblast apoE mRNA and protein levels were up-regulated during staurosporine-induced apoptosis and this was correlated with increased caspase-3 activity and apoptotic morphological alterations. Because the transcription of apoE and specific pro-apoptotic genes is regulated by the nuclear receptor LXR (liver X receptor) α, we analysed LXRα mRNA expression by quantitative real-time PCR and found it to be increased before apoE mRNA induction. The expression of ABCA1 (ATP-binding cassette transporter A1) mRNA, which is also regulated by LXRα, was increased in parallel with apoE mRNA, indicating that LXRα probably promotes apoE and ABCA1 transcription during apoptosis. Fibroblast apoE levels were increased under conditions of serum-starvation-induced growth arrest and hyperoxia-induced senescence. In both cases, an increased nuclear apoE level was observed, particularly in cells that accumulated lipofuscin. Nuclear apoE was translocated to the cytosol when mitotic nuclear disassembly occurred and this was associated with an increase in total cellular apoE levels. ApoE amino acid sequence analysis indicated several potential sites for phosphorylation. In vivo studies, using 32P-labelling and immunoprecipitation, revealed that fibroblast apoE can be phosphorylated. These studies reveal novel associations and potential roles for apoE in fundamental cellular processes.

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