Corbett J A, McDaniel M L
Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110.
J Exp Med. 1995 Feb 1;181(2):559-68. doi: 10.1084/jem.181.2.559.
Cytokines, released in and around pancreatic islets during insulitis, have been proposed to participate in beta-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 beta cells which results in the inhibition of beta 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 beta or alpha cells purified by fluorescence activated cell sorting (Facs). In contrast, IL-1 beta induces the expression of iNOS and also inhibits insulin secretion by both intact islets and Facs-purified beta cells, whereas TNF+LPS have no inhibitory effects on insulin secretion by purified beta 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 beta 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-1 alpha and IL-1 beta 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 beta 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 beta cell, which is selectively destroyed during the development of autoimmune diabetes.
在胰岛炎期间，胰岛及其周围释放的细胞因子被认为参与了与自身免疫性糖尿病相关的β细胞破坏。在本研究中，我们评估了以下假说：胰岛非内分泌细胞局部释放细胞因子白细胞介素1（IL-1）会诱导β细胞表达诱导型一氧化氮合酶（iNOS），进而导致β细胞功能受到抑制。用肿瘤坏死因子（TNF）和脂多糖（LPS）联合处理大鼠胰岛，已知这两种物质可激活巨噬细胞，能刺激iNOS的表达和亚硝酸盐的形成。尽管TNF+LPS可诱导完整胰岛表达iNOS并抑制胰岛素分泌，但这种组合不会诱导通过荧光激活细胞分选（Facs）纯化的β细胞或α细胞表达iNOS。相反，IL-1β可诱导iNOS的表达，同时抑制完整胰岛和Facs纯化的β细胞的胰岛素分泌，而TNF+LPS对纯化的β细胞的胰岛素分泌没有抑制作用。有证据表明，TNF+LPS通过刺激IL-1的释放来抑制胰岛的胰岛素分泌，随后IL-1会诱导β细胞表达iNOS。IL-1受体拮抗剂蛋白可完全阻止TNF+LPS诱导的胰岛素分泌抑制，并减弱胰岛中亚硝酸盐的形成，用针对IL-1α和IL-1β的抗血清中和IL-1可减弱TNF+LPS诱导的胰岛亚硝酸盐形成。iNOS和胰岛素的免疫组织化学定位证实，TNF+LPS可诱导胰岛β细胞表达iNOS，并且一小部分不含胰岛素的细胞也表达iNOS。胰岛内IL-1的局部释放似乎是TNF+LPS诱导胰岛素分泌抑制所必需的，因为TNF+LPS不会刺激物理分离成单个细胞的胰岛形成亚硝酸盐。这些发现首次证明，数量有限的非内分泌细胞能够在胰岛中释放足够量的IL-1，以诱导iNOS表达并抑制β细胞功能，而β细胞在自身免疫性糖尿病发展过程中会被选择性破坏。
