Ghrelin Suppression of Helicobacter pylori-Induced Gastric Mucosal Expression of iNOS is Mediated through the Inhibition of IKK-β Activation by cNOS-Dependent S-Nitrosylation

Excessive nitric oxide generation, caused by the disturbances in nitric oxide synthase (NOS) isozyme system, plays a key role in defining the extent of gastric mucosal inflammatory response to H. Pylori infection. Here, we report that H. Pylori LPS-induced enhancement in gastric mucosal inducible (i) iNOS expression and the impairment in constitutive (c) cNOS activity was associated with up-regulation in the inhibitory kB kinase-β (IKKβ) activation through phosphorylation, rise in IκB-α degradation, and the increase in the transcriptional factor, NF-κB, nuclear translocation. Further, we show that the countering effect of peptide hormone, ghrelin, on the LPS-induced disturbances in NOS isozyme system was reflected in the increase in Src/Akt-dependent cNOS activation through phosphorylation and the suppression of IKK-β activity through cNOSmediated IKK-β protein S-nitrosylation. As a consequence, ghrelin exerted the inhibitory effect on the LPS-induced rise in IκB-α degradation and NF-κB nuclear translocation, thus leading to iNOS gene suppression and the repression of iNOS induction. These results point to a central role of cNOS activation in controlling the signaling pathways of the LPS-triggered iNOS gene induction. Moreover, our findings suggest a molecular mechanism by which ghrelin suppresses the gastric mucosal proinflammatory consequences of H. Pylori infection.