TNF-alpha and IFN-gamma potentiate the deleterious effects of IL-1 beta on mouse pancreatic islets mainly via generation of nitric oxide.
Cytokines may be important mediators of beta-cell damage in early insulin-dependent diabetes mellitus. In order to further characterize the mechanism(s) of action of cytokines on insulin-producing cells, mouse pancreatic islets were exposed for 48 h to IL-1 beta, IFN-gamma or TNF-alpha, alone or in combinations. The three cytokines induced islet nitric oxide (NO) production, an effect most marked when islets were exposed to the three cytokines together. In parallel with NO production, IL-1 beta+IFN-gamma+TNF-alpha impaired islet function, as judged by decreased islet DNA and insulin content, decreased glucose metabolism and decreased glucose-induced insulin release. Aminoguanidine, an inhibitor of NO production, prevented all the above described suppressive effects of the cytokines, with exception of depletion in islet insulin content. In parallel experiments, insulin-producing RIN cells were exposed for 6 h to the same cytokines. Both IL-1 beta and TNF-alpha, but not IFN-gamma, induced NO production and expression of the mRNA encoding for the inducible form of the enzyme NO synthase (iNOS). These effects were most pronounced when combinations of IL-1 beta+IFN-gamma or IL-1 beta+IFN-gamma+TNF-alpha were used. As a whole, the data suggest that combinations of cytokines induce higher amounts of NO generation by mouse pancreatic islets than each of the cytokines isolated. An important source of islet NO production are probably the beta-cells, as pointed by data obtained with an insulinoma cell line. Most of the deleterious effects of the cytokines of mouse islets are prevented by blocking NO production, suggesting that NO is the main mediator of cytokine-induced beta-cell damage.(ABSTRACT TRUNCATED AT 250 WORDS)
Cetkovic-Cvrlje
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Department of Medical Cell Biology, Uppsala University, Sweden.
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D000818:Animals; D004357:Drug Synergism; D005069:Evaluation Studies as Topic; D006146:Guanidines; D007340:Insulinoma / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology*; D007375:Interleukin-1 / Q000633:toxicity*; D007515:Islets of Langerhans / Q000187:drug effects*; D051379:Mice; D009569:Nitric Oxide / Q000096:biosynthesis* / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D006146:Guanidines; D007375:Interleukin-1; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D007371:Interferon-gamma; C004479:pimagedine