Intraislet release of interleukin 1 inhibits β cell function by inducing β cell expression of inducible nitric oxide synthase

Abstract

Cytokines, released in and around pancreatic islets during insulitis, have been proposed to participate in β-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 β cells which results in the inhibition of β 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 of iNOS 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 β or α cells purified by fluorescence activated cell sorting (Facs). In contrast, IL-1β induces the expression of iNOS and also inhibits insulin secretion by both intact islets and Facs-purified β cells, whereas TNF+LPS have no inhibitory effects on insulin secretion by purified β 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 β 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 IL-1α and IL-1β attenuates TNF + LPS-induced nitrite formation by islets. Immunohistochemical localization of iNOS and insulin confirm that TNF+LPS induce the expression of iNOS by islet β 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 β cell, which is selectively destroyed during the development of autoimmune diabetes.