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Involvement of p38 MAPK-dependent activator protein (AP-1) activation in modulation of gastric mucosal inflammatory responses to Helicobacter pylori by ghrelin

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Abstract

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.

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  1. 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

    B. L. Slomiany & A. Slomiany

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  1. B. L. Slomiany
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  2. A. Slomiany
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Correspondence to B. L. Slomiany.

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Slomiany, B.L., Slomiany, A. Involvement of p38 MAPK-dependent activator protein (AP-1) activation in modulation of gastric mucosal inflammatory responses to Helicobacter pylori by ghrelin. Inflammopharmacol 21, 67–78 (2013). https://doi.org/10.1007/s10787-012-0141-9

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