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

Bronislaw L. Slomiany, Amalia Slomiany

Research Center, University of Medicine and Dentistry of New Jersey, Newark, USA.

DOI: 10.4236/ajmb.2012.22013                

Abstract

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.

Keywords

H. pylori; Gastric Mucosa; iNOS Induction; COX-2 Activation; Ghrelin; cNOS Phosphorylation; IKK-β; S-Nitrosylation

Conflicts of Interest

The authors declare no conflicts of interest.

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