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首页> 外文期刊>Journal of cellular biochemistry. >Exendin-4 inhibits iNOS expression at the protein level in LPS-stimulated Raw264.7 macrophage by the activation of cAMP/PKA pathway
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Exendin-4 inhibits iNOS expression at the protein level in LPS-stimulated Raw264.7 macrophage by the activation of cAMP/PKA pathway

机译：Exendin-4通过激活cAMP / PKA途径抑制LPS刺激的Raw264.7巨噬细胞中iNOS表达。

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Glucagon-like peptide-1 (GLP-1) and its potent agonists have been widely studied in pancreatic islet ??-cells. However, GLP-1 receptors are present in many extrapancreatic tissues including macrophages, and thus GLP-1 may have diverse actions in these tissues and cells. Therefore, we examined the mechanism by which exendin-4 (EX-4), a potent GLP-1 receptor agonist, inhibits lipopolysaccharide (LPS)-induced iNOS expression in Raw264.7 macrophage cells. EX-4 significantly inhibited LPS-induced iNOS protein expression and nitrite production. However, Northern blot and promoter analyses demonstrated that EX-4 did not inhibit LPS-induced iNOS mRNA expression and iNOS promoter activity. Electrophoretic mobility shift assay (EMSA) showed that EX-4 did not alter the binding activity of NF-??B to the iNOS promoter. Consistent with the result of EMSA, LPS-induced I??B?? phosphorylation and nuclear translocation of p65 were not inhibited by EX-4. Also, actinomycin D chase study and the promoter assay using the construct containing 3??-untranslated region of iNOS showed that EX-4 did not affect iNOS mRNA stability. Meanwhile, cycloheximide chase study demonstrated that EX-4 significantly accelerated iNOS protein degradation. The EX-4 inhibition of LPS-induced iNOS protein was significantly reversed by adenylate cyclase inhibitors (MDL-12330A and SQ 22536), a PKA inhibitor (H-89) and PKA?? gene silencing. These findings suggest that EX-4 inhibited LPS-induced iNOS expression at protein level, but not at transcriptional mechanism of iNOS gene and this inhibitory effect of EX-4 was mainly dependent on cAMP/PKA system. J. Cell. Biochem. 114: 844-853, 2013. ? 2012 Wiley Periodicals, Inc.
机译：胰高血糖素样肽-1（GLP-1）及其有效的激动剂已在胰岛β-细胞中得到广泛研究。但是，GLP-1受体存在于包括巨噬细胞在内的许多胰腺外组织中，因此GLP-1在这些组织和细胞中可能具有多种作用。因此，我们检查了有效的GLP-1受体激动剂exendin-4（EX-4）抑制脂多糖（LPS）诱导的Raw264.7巨噬细胞中iNOS表达的机制。 EX-4显着抑制LPS诱导的iNOS蛋白表达和亚硝酸盐生成。但是，Northern印迹和启动子分析表明，EX-4不会抑制LPS诱导的iNOS mRNA表达和iNOS启动子活性。电泳迁移率变动分析（EMSA）表明，EX-4没有改变NF-κB与iNOS启动子的结合活性。与EMSA的结果一致，LPS诱导的I ?? B ?? p-4的磷酸化和核易位没有受到EX-4的抑制。另外，放线菌素D追踪研究和使用含有iNOS的3′-非翻译区的构建体的启动子试验表明，EX-4不影响iNOS mRNA的稳定性。同时，环己酰亚胺的追踪研究表明EX-4显着加速了iNOS蛋白的降解。 LPS诱导的iNOS蛋白对EX-4的抑制作用被腺苷酸环化酶抑制剂（MDL-12330A和SQ 22536），PKA抑制剂（H-89）和PKA25显着逆转。基因沉默。这些发现表明EX-4在蛋白水平上抑制了LPS诱导的iNOS表达，但在iNOS基因的转录机制上却没有，并且EX-4的这种抑制作用主要取决于cAMP / PKA系统。 J.细胞。生化。 114：844-853，2013年。 2012 Wiley期刊公司

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