Peroxynitrite is a mediator of cytokine-induced destruction of human pancreatic islet β cells
Peroxynitrite is a mediator of cytokine-induced destruction of human pancreatic islet β cells
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DOI：
10.1038/labinvest.3780381
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发表时间：
2001-12-01
影响因子：
5
通讯作者：
Rabinovitch, A
中科院分区：
文献类型：
--
作者：
Lakey, JRT;Suarez-Pinzon, WL;Rabinovitch, A
促炎细胞因子白介素-1 β（IL-1 β）、肿瘤坏死因子α（TNF α）和干扰素γ（IFN γ）对胰岛β细胞具有细胞毒性，可能通过诱导β细胞中的一氧化氮和/或氧自由基产生。过氧亚硝酸盐是一氧化氮和超氧自由基的反应产物，是一种强氧化剂和细胞毒性介质;因此，我们假设过氧亚硝酸盐可能是奎宁诱导的胰岛β细胞破坏的介质。为了验证这一假设，我们将从人胰腺分离的胰岛与IL-1 β、TNF α和IFN γ的细胞因子组合孵育。我们发现，这些细胞因子诱导显著增加硝基酪氨酸，过氧亚硝酸盐的标记，在胰岛0细胞，和硝基酪氨酸的增加之前胰岛细胞的破坏。过氧亚硝酸盐模拟了细胞因子对硝基酪氨酸形成和胰岛β细胞破坏的影响。L-N-G-单甲基精氨酸是一种一氧化氮合酶抑制剂，可阻止精氨酸诱导的一氧化氮产生，但不能阻止过氧化氢产生、硝基酪氨酸形成或胰岛β细胞破坏。相反，胍基乙基二硫化物，一种诱导型一氧化氮合酶抑制剂和过氧亚硝酸盐清除剂，阻止了精氨酸诱导的一氧化氮和过氧化氢的产生、硝基酪氨酸的形成和胰岛β细胞的破坏。这些结果表明，奎宁诱导的过氧亚硝酸盐形成依赖于超氧化物（测量为过氧化氢）的产生增加，过氧亚硝酸盐是奎宁诱导的人胰岛β细胞破坏的介质。
The proinflammatory cytokines, interleukin-1 beta (IL-1 beta), tumor necrosis factor alpha (TNF alpha), and interferon gamma (IFN gamma), are cytotoxic to pancreatic islet beta cells, possibly by inducing nitric oxide and/or oxygen radical production in the beta cells. Peroxynitrite, the reaction product of nitric oxide and the superoxide radical, is a strong oxidant and cytotoxic mediator; therefore, we hypothesized that peroxynitrite might be a mediator of cytokine-induced islet beta -cell destruction. To test this hypothesis we incubated islets isolated from human pancreata with the cytokine combination of IL-1 beta, TNF alpha, and IFN gamma. We found that these cytokines induced significant increases in nitrotyrosine, a marker of peroxynitrite, in islet 0 cells, and the increase in nitrotyrosine preceded islet-cell destruction. Peroxynitrite mimicked the effects of cytokines on nitrotyrosine formation and islet beta -cell destruction. L-N-G-monomethyl arginine, an inhibitor of nitric oxide synthase, prevented cytokine-induced nitric oxide production but not hydrogen peroxide production, nitrotyrosine formation, or islet beta -cell destruction. in contrast, guanidinoethyldisulphide, an inhibitor of inducible nitric oxide synthase and scavenger of peroxynitrite, prevented cytokine-induced nitric oxide and hydrogen peroxide production, nitrotyrosine formation, and islet beta -cell destruction. These results suggest that cytokine-induced peroxynitrite formation is dependent upon increased generation of superoxide (measured as hydrogen peroxide) and that peroxynitrite is a mediator of cytokine-induced destruction of human pancreatic islet beta cells.