TY - JOUR
T1 - Involvement of p38 MAPK-dependent activator protein (AP-1) activation in modulation of gastric mucosal inflammatory responses to Helicobacter pylori by ghrelin
AU - Slomiany, B. L.
AU - Slomiany, A.
PY - 2013/2
Y1 - 2013/2
N2 - 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 signalregulated kinase and p38 activation, and occurred with the involvement of transcription factors, CCATT/enhancerbinding protein (C/EBP) d, cAMP response element-binding protein, activator protein-1 (AP-1), and NF-jB. The modulatory effect of ghrelin on the LPS-induced changes was manifested in the inhibition of nuclear translocation of p65 NF-jB and C/EBPd, 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-b 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.
AB - 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 signalregulated kinase and p38 activation, and occurred with the involvement of transcription factors, CCATT/enhancerbinding protein (C/EBP) d, cAMP response element-binding protein, activator protein-1 (AP-1), and NF-jB. The modulatory effect of ghrelin on the LPS-induced changes was manifested in the inhibition of nuclear translocation of p65 NF-jB and C/EBPd, 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-b 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.
KW - AP-1
KW - COX
KW - Gastric mucosa
KW - Ghrelin
KW - H. pylori
KW - NF-jB
KW - NOS
KW - P38 kinase
KW - S-nitrosylation
UR - http://www.scopus.com/inward/record.url?scp=84873413847&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84873413847&partnerID=8YFLogxK
U2 - 10.1007/s10787-012-0141-9
DO - 10.1007/s10787-012-0141-9
M3 - Article
C2 - 22669511
AN - SCOPUS:84873413847
SN - 0925-4692
VL - 21
SP - 67
EP - 78
JO - Inflammopharmacology
JF - Inflammopharmacology
IS - 1
ER -