Among the key factors defining the extent of gastric mucosal inflammatory involvement in response to H. pylori is the excessive generation of prostaglandin (PGE2) and nitric oxide (NO), caused by the overexpression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), and triggered by the activation of MAPK/JNK, p38 and ERK, and nuclear translocation of the cognate transcription factors. In this study, we report on the role of MAPK/ERK in the regulation of H. pylori LPS-induced gastric mucosal expression of COX-2 and iNOS. We show that ERK activation by the LPS leads to phosphorylation of the inhibitory κB kinase-β (IKK-β) and cytosolic phospholipase A2 (cPLA2), and is reflected in the upsurge in NF-κB nuclear translocation, induction in COX-2 and iNOS expression, and up-regulation in cPLA2 activity. The modulatory effect of peptide hormone, ghrelin, on the LPS-induced changes, although associated with further enhancement in ERK, IKK-β and cPLA2 phosphorylation, was reflected in the suppression of IKK-β and cPLA2 activity through S-nitrosylation. While the effect of ghrelin on S-nitrosylation was susceptible to suppression by the inhibitors of Src/Akt pathway, the inhibition of ERK activation caused the blockage in IKK-β and cPLA2 phosphorylation as well as S-nitrosylation. Taken together, our data show that H. pylori-induced ERK activation plays a critical role in up-regulation of gastric mucosal PGE2 and NO generation at the level of IKK-β and cPLA2 activation, and that ghrelin counters these proinflammatory consequences of the LPS through Src/Akt-dependent S-nitrosylation.
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