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.