IL-1 produced and released endogenously within human islets inhibits β cell function
IL-1 produced and released endogenously within human islets inhibits β cell function
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DOI：
10.1172/jci844
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发表时间：
1998-08-01
影响因子：
15.9
通讯作者：
Corbett, JA
中科院分区：
文献类型：
--
作者：
Arnush, M;Heitmeier, MR;Corbett, JA
在自身免疫性糖尿病的发展过程中，常驻巨噬细胞参与了β细胞损伤的启动，本研究的目的是确定常驻巨噬细胞在人朗格汉斯胰岛内源性产生和释放白细胞介素1 （IL-1）是否导致β细胞功能的抑制。用肿瘤坏死因子(TNF) +脂多糖(LPS) +干扰素- γ (ifn - γ)联合治疗人胰岛可刺激诱导型一氧化氮合酶（iNOS）表达、一氧化氮产生并抑制葡萄糖刺激的胰岛素分泌。IL-1受体拮抗剂蛋白（IRAP）可抑制TNF + LPS + ifn - γ诱导的iNOS表达和亚硝酸盐的产生，并减弱对葡萄糖刺激的胰岛胰岛素分泌的抑制作用，氨基胍抑制iNOS活性也可减弱TNF + LPS + ifn - γ诱导的胰岛胰岛素分泌的抑制作用，这些结果表明TNF + LPS + ifn - γ的抑制作用是由一氧化氮介导的。由人胰岛内源性释放的IL-1作用产生，逆转录酶聚合酶链反应证实TNF + LPS + ifn - γ刺激人胰岛IL-1 α和IL-1 β表达。两种形式的证据表明，常驻巨噬细胞是人胰岛细胞IL-1的来源：消耗胰岛淋巴样细胞的培养条件阻止TNF + LPS + ifn - γ诱导的iNOS表达、一氧化氮的产生和人胰岛IL-1 mRNA的表达；通过免疫组织化学分析，IL-1和巨噬细胞表面标志物CD69在TNF + LPS + ifn - γ处理的人胰岛中共定位。最后，人类胰岛中TNF + LPS + ifn - γ诱导的IL-1释放不需要一氧化氮的产生。然而，细胞损伤刺激胰岛巨噬细胞释放IL-1。这些发现支持了一种假设，即激活的胰岛巨噬细胞可能在胰岛素依赖型糖尿病的发展过程中通过在人胰岛释放IL-1介导β细胞损伤，随后细胞因子诱导β细胞表达iNOS。
Resident macrophages have been suggested to participate in the initiation of beta cell damage during the development of autoimmune diabetes, The purpose of this study was to determine if the endogenous production and release of interleukin 1 (IL-1) in human islets of Langerhans by resident macrophages results in the inhibition of beta cell function. Treatment of human islets with a combination of tumor necrosis factor (TNF) + lipopolysaccharide (LPS) + interferon-gamma (IFN-gamma) stimulates 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-induced iNOS expression and nitrite production, and attenuates the inhibitory 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 islets, These results indicate that the inhibitory effects of TNF + LPS + IFN-gamma are mediated by nitric oxide, produced by the actions of IL-1 released endogenously within human islets, Reverse transcriptase polymerase chain reaction was used to confirm that TNF + LPS + IFN-gamma stimulates the expression of both IL-1 alpha and IL-1 beta in human islets. Two forms of evidence indicate that resident macrophages are the human islet cellular source of IL-1: culture conditions that deplete islet lymphoid cells prevent TNF + LPS + IFN-gamma-induced iNOS expression, 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 immunohistochemical 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 findings support the hypothesis that activated islet macrophages may mediate beta cell damage during the development of insulin-dependent diabetes by releasing IL-1 in human islets followed by cytokine-induced iNOS expression by beta cells.