Evidence for IL-6 production by and effects on the pancreatic beta-cell.
IFN-gamma and TNF-alpha injure the pancreatic beta-cell and may be involved in the pathogenesis of autoimmune type 1 diabetes. Because the induction of IL-6 appears to be an important host cell response to injury, we have examined whether IL-6 is produced by murine pancreatic islets or rat insulinoma (RIN-m5F) cells after their exposure to IFN-gamma and TNF-alpha. Islet culture supernatants contained detectable IL-6 activity which was increased 6-fold when islets were exposed to IFN-gamma and 40- and 115-fold when islets were exposed to TNF-alpha and TNF-alpha + IFN-gamma, respectively. A mAb against murine IL-6 abolished (control and IFN-gamma) or significantly reduced (TNF-alpha and TNF-alpha + IFN-gamma) the IL-6 activity in islet supernatants. The magnitude for the effects of IFN-gamma and TNF-alpha on the production of IL-6 from mouse islets was found to be both time and dose dependent. Northern blot hybridization analysis of islet total cytoplasmic RNA with a cDNA probe to murine IL-6 revealed a band at 1.3 kb, the intensity of which increased in islets exposed to IFN-gamma + TNF-alpha. IL-6 activity was also detected in culture supernatants from RIN-m5F cells exposed to TNF-alpha + IFN-gamma. Islets cultured with rIL-6 secreted higher levels of insulin compared with control islets. Pancreatic islet cells, in all probability beta-cells, produce IL-6, the expression of which is up-regulated by IFN-gamma and/or TNF-alpha. In addition to a possible role in regulating pancreatic beta-cell function we propose that IL-6 produced by the pancreatic beta-cell may act as a costimulator for autoreactive B and T lymphocytes in autoimmune diabetes.
Campbell
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Burnet Clinical Research Unit, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
Cutri
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Wilson
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Harrison
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D000818:Animals; D015152:Blotting, Northern; D002474:Cell-Free System; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D006367:HeLa Cells / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D015850:Interleukin-6; D007378:Interleukins / Q000096:biosynthesis* / Q000276:immunology / Q000502:physiology; D007515:Islets of Langerhans / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
D015850:Interleukin-6; D007378:Interleukins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma