Modulation of gastric mucosal inflammatory responses to <i>Helicobacter pylori</i>by ghrelin: Role of cNOS-dependent IKK-<i>β</i>S-nitrosylation in the regulation of COX-2 activation

• 作者: Amalia Slomiany Bronislaw L. Slomiany
• 来源期刊: 美国分子生物学期刊(英文)
• 学科: 医学
• 关键词: H. pylori Gastric Mucosa iNOS Induction COX-2 ACTIVATION GHRELIN cNOS Phosphorylation IKK-β S-NITROSYLATION
• 年，卷（期）: 2012,（2）
• 页码范围: 113-123
• 页数: 11页
• 分类号: R73

摘要

Disturbances in nitric oxide synthase (NOS) and cyclooxygenase (COX) isozyme systems, manifested by the excessive NO and prostaglandin (PGE2) generation, are well-recognized features of gastric mucosal inflammatory responses to H. pylori infection. In this study, we report that H. pylori LPS-induced enhancement in gastric mucosal inducible (i) iNOS expression and COX-2 activation was accompanied by the impairment in constitutive (c) cNOS phosphorylation, up-regulation in the inhibitory κB kinase-β (IKKβ) activation and the increase in the transcriptional factor, NF-κB, nuclear translocation. Further, we show that abrogation of cNOS control over NF-κB activation has lead to induction of iNOS expression and COX-2 activation through S-nitrosylation. Moreover, we demonstrate that the modulatory effect of peptide hormone, ghrelin, on the LPS-induced changes was reflected in the increase in Src/Akt-dependent cNOS activation through phosphorylation and the suppression of IKK-β activity through cNOS-mediated IKK-β protein S-nitrosylation. As a result, ghrelin exerted the inhibitory effect on NF-κB nuclear translocation, thus causing the repression of iNOS gene induction and the inhibition in COX-2 activation through iNOS-dependent S-nitrosylation. Our findings point to cNOS activation as a pivotal element in the signaling cascade by which ghrelin exerts modulatory control over proinflammatory events triggered in gastric mucosa by H. pylori infection.