IL-1 PRODUCED AND RELEASED ENDOGENOUSLY WITHIN HUMAN ISLETS INHIBITS BETA-CELL FUNCTION

Resident macrophages have been suggested to participate in the initiat ion of beta cell damage during the development of autoimmune diabetes, The purpose of this study was to determine if the endogenous producti on and release of interleukin 1 (IL-1) in human islets of Langerhans b y resident macrophages results in the inhibition of beta cell function . Treatment of human islets with a combination of tumor necrosis facto r (TNF) + lipopolysaccharide (LPS) + interferon-gamma (IFN-gamma) stim ulates inducible nitric oxide synthase (iNOS) expression, nitric oxide production, and inhibits glucose-stimulated insulin secretion. The IL -1 receptor antagonist protein (IRAP) prevents TNF + LPS + IFN-gamma-i nduced iNOS expression and nitrite production, and attenuates the inhi bitory effects on glucose-stimulated insulin secretion by human islets , Inhibition of iNOS activity by aminoguanidine also attenuates TNF LPS + IFN-gamma-induced inhibition of insulin secretion by human islet s, These results indicate that the inhibitory effects of TNF + LPS + I FN-gamma are mediated by nitric oxide, produced by the actions of IL-1 released endogenously within human islets, Reverse transcriptase poly merase chain reaction was used to confirm that TNF + LPS + IFN-gamma s timulates the expression of both IL-1 alpha and IL-1 beta in human isl ets. Two forms of evidence indicate that resident macrophages are the human islet cellular source of IL-1: culture conditions that deplete i slet lymphoid cells prevent TNF + LPS + IFN-gamma-induced iNOS express ion, nitric oxide production, and IL-1 mRNA expression by human islets ; and IL-1 and the macrophage surface marker CD69 colocalize in human islets treated with TNF + LPS + IFN-gamma as determined by immunohisto chemical analysis. Lastly, nitric oxide production is not required for TNF + LPS + IFN-gamma-induced IL-1 release in human islets. However, cellular damage stimulates IL-1 release by islet macrophages. These fi ndings support the hypothesis that activated islet macrophages may med iate beta cell damage during the development of insulin-dependent diab etes by releasing IL-1 in human islets followed by cytokine-induced iN OS expression by beta cells.