title: IL-1beta, IFN-gamma and TNF-alpha increase vulnerability of pancreatic beta cells to autoimmune destruction.
abstract: In the pathogenesis of type-1 diabetes insulin-producing beta-cells are destroyed by cellular autoimmune processes. The locality of beta-cell destruction is the inflamed pancreatic islet. During insulitis cytokines released from islet-infiltrating mononuclear cells affect beta-cells at several levels. We investigated whether cytokine-induced beta-cell destruction is associated with changes in the expression of the surface receptors intercellular adhesion molecule (ICAM)-1 and Fas. Islets from diabetes-prone and congenic diabetes-resistant BB rats were exposed to interleukin (IL)-1beta alone or in combination with interferon (IFN)-gamma plus tumour necrosis factor (TNF)-alpha. Cytokines decreased islet insulin content, suppressed glucose stimulated insulin secretion and generated enhanced amounts of nitric oxide and DNA-strand breaks. While no membrane alterations of IL-1beta treated islets cells were detectable, the cytokine combination caused damage of cell membranes. Independent of diabetes susceptibility IL-1beta treated islet beta-cells expressed a significantly increased amount of ICAM-1 on their surfaces which was not further increased by IFN-gamma+TNF-alpha. However, IL-1beta induced Fas expression was significantly enhanced only on beta-cells from diabetes-prone BB rats. From these results we suggest that IL-1beta mediates the major stimulus for ICAM-1 induction which is possibly a necessary but not sufficient step in the process of beta-cell destruction. Obviously, the additional enhancement of Fas expression on the surface of beta-cells is important for destruction. The combined action of all three cytokines induced the expression of Fas on the beta-cell surface independent of diabetes susceptibility, indicating that such a strong stimulus in vitro may induce processes different from the precise mechanisms of beta-cell destruction in vivo.
authors.affiliation: Institute of Pathophysiology, Ernst-Moritz-Arndt-University of Greifswald, Greifswalder Strasse 11b, Karlsburg 17495, Germany. wachlin@uni-greifswald.de
authors.forename: Gerhild
authors.initials: G
authors.lastname: Wachlin
authors.forename: Petra
authors.initials: P
authors.lastname: Augstein
authors.forename: Dieter
authors.initials: D
authors.lastname: Schröder
authors.forename: Beate
authors.initials: B
authors.lastname: Kuttler
authors.forename: Ingrid
authors.initials: I
authors.lastname: Klöting
authors.forename: Peter
authors.initials: P
authors.lastname: Heinke
authors.forename: Siegfried
authors.initials: S
authors.lastname: Schmidt
mesh_terms: D000818:Animals; D020296:Animals, Congenic; D015551:Autoimmunity / Q000187:drug effects*; D004249:DNA Damage; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology / Q000276:immunology; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology*; D007375:Interleukin-1 / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000187:drug effects* / Q000276:immunology*; D009573:Nitrites / Q000378:metabolism; D051381:Rats; D011913:Rats, Inbred BB; D011994:Recombinant Proteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D019014:fas Receptor / Q000378:metabolism
chemical_list: D007328:Insulin; D007375:Interleukin-1; D009573:Nitrites; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D018799:Intercellular Adhesion Molecule-1; D007371:Interferon-gamma