Interleukin-1β-induced rat pancreatic islet nitric oxide synthesis requires both the p38 and extracellular signal-regulated kinase 1/2 mitogen-activated protein kinases
Interleukin-1β-induced rat pancreatic islet nitric oxide synthesis requires both the p38 and extracellular signal-regulated kinase 1/2 mitogen-activated protein kinases
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DOI：
10.1074/jbc.273.24.15294
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发表时间：
1998-06-12
影响因子：
4.8
通讯作者：
Mandrup-Poulsen, T
中科院分区：
文献类型：
--
作者：
Larsen, CM;Wadt, KAW;Mandrup-Poulsen, T
白细胞介素1β(IL-1β)通过抑制葡萄糖氧化、引起DNA损伤和诱导细胞凋亡而对大鼠胰岛β细胞产生细胞毒作用，一氧化氮(NO)是这些作用的必要但不充分的介导物。IL-1β诱导大鼠胰岛对Elk-1、激活转录因子2、c-jun和热休克蛋白25的激活。用磷酸化抗体免疫印迹和免疫复合酶试验证实，IL-1β能激活胰岛和大鼠胰岛素瘤细胞的细胞外信号调节激酶(ERK)1/2和p38丝裂原活化蛋白激酶(P38)。特异性ERK1/2和p38抑制剂单独抑制IL-1β诱导的胰岛NO合成，但联合阻断IL-1β诱导的胰岛NO合成，逆转录-聚合酶链式反应显示ERK1/2和p38在转录水平控制IL-1β诱导的胰岛NO合成酶的表达。高渗诱导的胰岛细胞中ELK-1、激活转录因子2和热休克蛋白25的磷酸化以及ERK1/2和p38的激活与IL-1β诱导的相似，但不导致NO的合成。抑制p38而不是抑制ERK1/2可减弱IL-1β对葡萄糖刺激的胰岛素释放的抑制作用，我们得出结论：ERK1/2和p38的激活对IL-1β介导的β细胞NO合成是必要的，但不是充分的，p38参与了IL-1β的NO非依赖性作用的信号转导。
Interleukin-1 beta (IL-1 beta) is cytotoxic to rat pancreatic beta-cells by inhibiting glucose oxidation, causing DNA damage and inducing apoptosis, Nitric oxide (NO) is a necessary but not sufficient mediator of these effects. IL-1 beta induced kinase activity toward Elk-1, activation transcription factor 2, c-Jun, and heat shock protein 25 in rat islets. By Western blotting with phosphospecific antibodies and by immunocomplex kinase assay, IL-1 beta was shown to activate extracellular signal-regulated kinase (ERK) 1/2 and p38 mitogen-activated protein kinase (p38) in islets and rat insulinoma cells. Specific ERK1/2 and p38 inhibitors individually reduced but in combination blocked IL-1 beta-mediated islet NO synthesis, and reverse transcription-polymerase chain reaction of inducible NO synthase mRNA showed that ERK1/2 and p38 controlled IL-1 beta-induced islet inducible NO synthase expression at the transcriptional level. Hyperosmolarity caused phosphorylation of Elk-1, activation transcription factor 2, and heat shock protein 25 and activation of ERK1/2 and p38 in islets comparable to that induced by IL-1 beta but did not lead to NO synthesis. Inhibition of p38 but not of ERK1/2 attenuated IL-1 beta-mediated inhibition of glucose-stimulated insulin release, We conclude that ERK1/2 and p38 activation is necessary but not sufficient for IL-1 beta-mediated beta-cell NO synthesis and that p38 is involved in signaling of NO-independent effects of IL-1 beta in beta-cells.