Intraislet Release of Interleukin 1 Inhibits 3 Cell Function by Inducing 3 Cell Expression of Inducible Nitric Oxide Synthase

Cytokines, released in and around pancreatic islets during insulitis, have been proposed to participate in B-cell destruction associated with autoimmune diabetes. In this study we have evaluated the hypothesis that local release of the cytokine interleukin 1 (IL-1) by nonendocrine cells of the islet induce the expression of inducible nitric oxide synthase (iNOS) by 3 cells which results in the inhibition of 3 cell function. Treatment of rat islets with a combination of tumor necrosis factor (TNF) and lipopolysaccharide (LPS), conditions known to activate macrophages, stimulate the expression ofiNOS and the formation of nitrite. Although TNF + LPS induce iNOS expression and inhibit insulin secretion by intact islets, this combination does not induce the expression of iNOS by 3 or o~ cells purified by fluorescence activated cell sorting (Facs). In contrast, IL-13 induces the expression of iNOS and also inhibits insulin secretion by both intact islets and Facspurified 3 cells, whereas TNF+LPS have no inhibitory effects on insulin secretion by purified 3 cells. Evidence suggests that TNF+LPS inhibit insulin secretion from islets by stimulating the release of IL-1 which subsequently induces the expression of iNOS by 3 cells. The IL-1 receptor antagonist protein completely prevents TNF+ LPS-induced inhibition of insulin secretion and attenuates nitrite formation from islets, and neutralization of IL-1 with antisera specific for IL1 oL and IL13 attenuates TNF + LPS-induced nitrite formation by islet s. Immunohistochemical localization of iNOS and insulin confirm that TNF+LPS induce the expression of iNOS by islet 3 cells, and that a small percentage of noninsulin-containing cells also express iNOS. Local release of IL-1 within islets appears to be required for TNF+LPS-induced inhibition of insulin secretion because TNF+LPS do not stimulate nitrite formation from islets physically separated into individual cells. These findings provide the first evidence that a limited number of nonendocrine cells can release sufficient quantities of IL-1 in islets to induce iNOS expression and inhibit the function of the 3 cell, which is selectively destroyed during the development of autoimmune diabetes.