Interferon-gamma increases the sensitivity of islets of Langerhans for inducible nitric-oxide synthase expression induced by interleukin 1
Interferon-gamma increases the sensitivity of islets of Langerhans for inducible nitric-oxide synthase expression induced by interleukin 1
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DOI：
10.1074/jbc.272.21.13697
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发表时间：
1997-05-23
影响因子：
4.8
通讯作者：
Corbett, JA
中科院分区：
文献类型：
--
作者：
Heitmeier, MR;Scarim, AL;Corbett, JA
本研究的目的是评估干扰素- γ (ifn - γ)单独和联合白细胞介素-1 β (IL-1 β)对朗格汉斯胰岛诱导型一氧化氮合成酶（iNOS） mRNA和蛋白表达、亚硝酸盐产生和胰岛素分泌的影响。用IL-1 β处理大鼠胰岛导致亚硝酸盐产生的浓度依赖性增加，在5单位/ml时最大。单独，0.1单位/ml IL-1 β或150单位/ml大鼠ifn - γ不刺激大鼠胰岛iNOS表达或亚硝酸盐产生；然而，这些细胞因子结合起来，诱导iNOS的表达和亚硝酸盐的产生，其量级与5单位/ml IL-1 β的个体效应相似。胰岛素依赖型糖尿病期间选择性破坏的胰岛β细胞似乎是iNOS的一个胰岛细胞来源，因为150单位/ml的大鼠ifn - γ和0.1单位/ml的IL-1 β在通过荧光激活细胞分选纯化的原代β细胞和大鼠胰岛素瘤细胞系中诱导了类似的作用。在150单位/ml大鼠ifn - γ和0.1单位/ml IL-1 β的作用下，大鼠胰岛iNOS的表达和亚硝酸盐的产生与iNOS抑制剂氨基胍阻止胰岛素分泌和胰岛变性相关。ifn - γ增加β细胞对il -1诱导的iNOS表达敏感性的机制似乎与iNOS mRNA稳定性的增加有关。最后，在外源性添加的大鼠ifn - γ存在的情况下，胰岛物理分散过程中的细胞损伤导致足够数量的IL-1 β的释放，从而诱导iNOS表达和亚硝酸盐的产生。在这些条件下，IL-1 β的细胞来源被认为是常驻胰岛巨噬细胞，因为巨噬细胞在分散之前的消耗阻止了ifn - γ诱导的iNOS表达和分散的胰岛细胞形成亚硝酸盐。这些研究表明，T淋巴细胞细胞因子IFN-1 β使大鼠胰岛对IL-对iNOS表达和亚硝酸盐产生的影响的敏感性提高了10倍，部分原因是通过稳定iNOS mRNA。我们的研究还支持ifn - γ的效应作用，与常驻胰岛巨噬细胞释放IL-1 β一致，在自身免疫性糖尿病发展过程中介导β细胞破坏。
The purpose of this study was to evaluate the effects of interferon-gamma (IFN-gamma) alone and in combination with interleukin 1 beta (IL-1 beta) on inducible nitric-oxide synthase (iNOS) mRNA and protein expression, nitrite production, and insulin secretion by islets of Langerhans. Treatment of rat islets with IL-1 beta results in a concentration-dependent increase in the production of nitrite that is maximal at 5 units/ml. Individually, 0.1 unit/ml IL-1 beta or 150 units/ml rat IFN-gamma do not stimulate iNOS expression or nitrite production by rat islets; however, in combination, these cytokines induce the expression of iNOS and the production of nitrite to levels similar in magnitude to the individual effects of 5 units/ml IL-1 beta. The islet beta-cell, selectively destroyed during insulin-dependent diabetes mellitus, appears to be one islet cellular source of iNOS as 150 units/ml rat IFN-gamma and 0.1 unit/ml IL-1 beta induced similar effects in primary beta-cells purified by fluorescence-activated cell sorting and in the rat insulinoma cell line, RINm5F. iNOS expression and nitrite production by rat islets in response to 150 units/ml rat IFN-gamma and 0.1 unit/ml IL-1 beta are correlated with an inhibition of insulin secretion and islet degeneration that are prevented by the iNOS inhibitor aminoguanidine. The mechanism by which IFN-gamma increases the sensitivity of beta-cells for IL-1-induced iNOS expression appears to be associated with an increase in the stability of iNOS mRNA. Last, cellular damage during physical dispersion of islets results in the release of sufficient amounts of IL-1 beta to induce iNOS expression and nitrite production in the presence of exogenously added rat IFN-gamma. The cellular source of IL-1 beta under these conditions is believed to be resident islet macrophages as depletion of macrophages prior to dispersion prevents IFN-gamma-induced iNOS expression and nitrite formation by dispersed islet cells, These studies show that the T lymphocyte cytokine, IFN-1 beta increases the sensitivity of rat islets to the effects of IL- on iNOS expression and nitrite production by 10-fold, in part, through the stabilization of iNOS mRNA. Our studies also support an effector role for IFN-gamma, in concert with resident islet macrophage release of IL-1 beta, in mediating beta-cell destruction during the development of autoimmune diabetes.