NITRIC-OXIDE MEDIATES CYTOKINE-INDUCED INHIBITION OF INSULIN-SECRETION BY HUMAN ISLETS OF LANGERHANS
NITRIC-OXIDE MEDIATES CYTOKINE-INDUCED INHIBITION OF INSULIN-SECRETION BY HUMAN ISLETS OF LANGERHANS
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DOI：
10.1073/pnas.90.5.1731
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发表时间：
1993-03-01
影响因子：
11.1
通讯作者：
MCDANIEL, ML
中科院分区：
文献类型：
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作者：
CORBETT, JA;SWEETLAND, MA;MCDANIEL, ML
细胞因子被认为是介导与胰岛素依赖型糖尿病相关的β细胞破坏的免疫效应分子。在这篇报道中，我们证明了人重组白介素1β(IL-1β)、肿瘤坏死因子α(TNF-α)和干扰素-γ(干扰素-γ)的细胞因子组合诱导人胰岛产生一氧化氮。这种细胞因子的组合既刺激了一氧化氮衍生物亚硝酸盐的形成，也刺激了人类胰岛cGMP的积累。一氧化氮合酶抑制剂N(G)-单甲基-L-精氨酸可防止cGMP和亚硝酸盐的形成。IL-1β和干扰素-γ足以诱导人胰岛产生一氧化氮，而肿瘤坏死因子-α则促进亚硝酸盐的产生。这种细胞因子(IL-1β、肿瘤坏死因子-α和干扰素-γ)的组合也会影响人类胰岛的胰岛素分泌。用低浓度的这种细胞因子组合(IL-1β15个单位/毫升，0.7 nM肿瘤坏死因子-α0.7毫微米，干扰素-γ150个单位/毫升)对人胰岛进行预处理，似乎能轻微刺激胰岛素的分泌。较高浓度的IL-1β(75个单位/ml)、3.5nM肿瘤坏死因子-α(3.5nM肿瘤坏死因子-α)和干扰素-γ(750个单位/毫升)可抑制人胰岛胰岛素的分泌，N(G)-单甲基-L-精氨酸可阻断这种抑制作用。这种较高浓度的细胞因子还诱导人类胰岛形成电子顺磁共振可检测的g=2.04轴向特征，这是铁-二硫代二亚硝基复合体形成的特征。这种复合体的形成被N(G)-单甲基-L-精氨酸所阻止，从而证实了这种细胞因子组合诱导了人胰岛一氧化氮的形成。这些结果表明，一氧化氮介导了细胞因子对葡萄糖刺激的人胰岛胰岛素分泌的抑制作用，提示一氧化氮可能参与了与胰岛素依赖型糖尿病相关的β细胞功能障碍。
Cytokines have been implicated as immunological effector molecules that mediate beta cell destruction associated with insulin-dependent diabetes mellitus. In this report we demonstrate that the cytokine combination of human recombinant interleukin 1beta (IL-1beta), tumor necrosis factor a (TNF-alpha), and interferon gamma (IFN-gamma) induces the formation of nitric oxide by human islets. This combination of cytokines stimulates both the formation of the nitric oxide derivative, nitrite, and the accumulation of cGMPby human islets. The nitric oxide synthase inhibitor N(G)-monomethyl-L-arginine prevents formation of both cGMP and nitrite. IL-1beta and IFN-gamma are sufficient to induce nitric oxide formation by human islets, whereas TNF-alpha potentiates nitrite production. This combination of cytokines (IL-1beta, TNF-alpha, and IFN-gamma) also influences insulin secretion by human islets. Pretreatment of human islets with low concentrations of this cytokine combination (IL-1beta at 15 units/ml, 0.7 nM TNF-alpha, and IFN-gamma at 150 units/ml) appears to slightly stimulate insulin secretion. Higher concentrations (IL-1beta at 75 units/ml, 3.5 nM TNF-alpha, and IFN-gamma at 750 units/ml) inhibit insulin secretion from human islets, and the inhibitory effect is prevented by N(G)-Monomethyl-L-arginine. This higher concentration of cytokines also induces the formation of an electron paramagnetic resonance-detectable g = 2.04 axial feature by human islets that is characteristic of the formation of an iron-dithio-dinitrosyl complex. The formation of this complex is prevented by N(G)-Monomethyl-L-arginine, thus confirming that this cytokine combination induces the formation of nitric oxide by human islets. These results indicate that nitric oxide mediates the inhibitory effects of cytokines on glucose-stimulated insulin secretion by human islets and suggest that nitric oxide may participate in beta-cell dysfunction associated with insulin-dependent diabetes mellitus.