Role of epidermal growth factor receptor transactivation in PPAR gamma-dependent suppression of Helicobacter pylori interference with gastric mucin synthesis.
Peroxisome-proliferator-activated receptor gamma (PPARgamma) is recognized for its role in regulation of genes associated with inflammation, and its activation of phosphatidylinositol 3-kinase (PI3K) has emerged recently as an important regulator of mucosal responses to bacterial infection. In this study, we report that PPARgamma activation leading to the impedance of Helicobacter pylori lipopolysaccharide (LPS) inhibitory effect on salivary mucin synthesis requires epidermal growth factor receptor (EGFR) participation. Using gastric mucosal cells in culture, we show that activation of PPARgamma with a specific agonist, ciglitazone, prevents the LPS-induced reduction in mucin synthesis, and the effect is reflected in a marked decrease in apoptosis, caspase-3 activity and NO generation. The impedance by ciglitazone of the LPS-induced reduction in mucin synthesis was blunted (up to 65.8%) in a concentration-dependent fashion by a specific inhibitor of EGFR kinase, PD153035, as well as the PPARgamma antagonist BADGE, and wortmannin, an inhibitor of PI3K. Moreover, the inhibitory effect of ciglitazone on the LPS-induced reduction in mucin synthesis and upregulation in apoptosis, caspase-3 activity and NO generation was countered by PP2, a selective inhibitor of tyrosine kinase Src responsible for ligand-independent EGFR transactivation. These findings indicate that PPARgamma activation leading to the suppression of H. pylori LPS inhibition of gastric mucin synthesis involves Src kinase-dependent EGFR transactivation.
Slomiany
Bronislaw L
BL
Research Center, C875, University of Medicine and Dentistry of New Jersey Dental School, 110 Bergen Street, P.O. Box 1709, Newark, NJ 07103-2400, USA. slomiabr@umdnj.edu
Slomiany
Amalia
A
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D005752:Gastric Mucins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D016480:Helicobacter pylori / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism*; D047495:PPAR gamma / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D045162:Thiazolidinediones / Q000494:pharmacology; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology*
D004791:Enzyme Inhibitors; D005752:Gastric Mucins; D047495:PPAR gamma; D045162:Thiazolidinediones; D066246:ErbB Receptors; C039671:ciglitazone