Involvement of p38 MAPK-dependent activator protein (AP-1) activation in modulation of gastric mucosal inflammatory responses to Helicobacter pylori by ghrelin.
A peptide hormone, ghrelin, plays an important role in modulation of gastric mucosal inflammatory responses to Helicobacter pylori infection by controlling the cross-talk between nitric oxide synthase (NOS) and cyclooxygenase (COX) enzyme systems. In this study, we report that H. pylori LPS-elicited induction in gastric mucosal COX-2 and inducible (i) iNOS protein expression, and the impairment in constitutive (c) cNOS phosphorylation, was associated with mitogen-activated protein kinase, c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase and p38 activation, and occurred with the involvement of transcription factors, CCATT/enhancer-binding protein (C/EBP) δ, cAMP response element-binding protein, activator protein-1 (AP-1), and NF-κB. The modulatory effect of ghrelin on the LPS-induced changes was manifested in the inhibition of nuclear translocation of p65 NF-κB and C/EBPδ, and suppression in AP-1 activation, and the inhibition in phosphorylation of JNK and p38, as well as their respective downstream targets, c-Jun and ATF-2. However, only the inhibition of p38-mediated ATF-2 phosphorylation was reflected in the reduced expression of COX-2 protein. Further, the effect of ghrelin of the LPS-induced changes was reflected in the increase in Src/Akt-dependent cNOS activation through phosphorylation and the inhibition of cNOS-mediated IKK-β S-nitrosylation. Our findings indicate ghrelin counters the proinflammatory consequences of H. pylori by interfering with the p38/ATF-2-induced AP-1 activation in association with concurrent up-regulation in Src/Akt-dependent cNOS phosphorylation.
Research Center, Room C875, UMDNJ-NJ Dental School, University of Medicine and Dentistry of New Jersey, 110 Bergen Street, PO Box 1709, Newark, NJ 07103-2400, USA. slomiabr@umdnj.edu
B L
BL
Slomiany
A
A
Slomiany
D000818:Animals; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D005753:Gastric Mucosa / Q000382:microbiology / Q000473:pathology; D005786:Gene Expression Regulation; D054439:Ghrelin / Q000378:metabolism*; D016481:Helicobacter Infections / Q000503:physiopathology; D016480:Helicobacter pylori / Q000302:isolation & purification; D007249:Inflammation / Q000382:microbiology / Q000473:pathology*; D008070:Lipopolysaccharides; D016328:NF-kappa B / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D054439:Ghrelin; D008070:Lipopolysaccharides; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D048051:p38 Mitogen-Activated Protein Kinases