Src kinase-dependent epidermal growth factor receptor transactivation in PPARgamma ligand-induced suppression of Porphyromonas gingivalis interference with salivary mucin synthesis.
Peroxisome proliferator-activated receptor gamma (PPARgamma) has emerged recently as an important participant in the resolution of inflammation by conveying signals that lead to mitogen-activated protein kinase (MAPK) cascade activation. In this study, we report that PPARgamma activation leading to the impedance of P. gingivalis lipopolysaccharide (LPS) inhibitory effect on salivary mucin synthesis requires epidermal growth factor receptor (EGFR) participation. 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 countered (up to 68.9%) in a dose-dependent fashion by a specific inhibitor of EGFR kinase, PD153035, as well as wortmannin, an inhibitor of phosphatidylinositol 3-kinase (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 blunted by a selective inhibitor of tyrosine kinase Src, PP2, responsible for ligand-independent EGFR transactivation. These findings indicate that PPARgamma activation leading to the suppression of P. gingivalis LPS inhibition of salivary mucin synthesis involves Src kinase-dependent EGFR transactivation.
Slomiany
Bronislaw L
BL
Research Center, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103-2400, USA. slomiabr@umdnj.edu
Slomiany
Amalia
A
D000818:Animals; D066246:ErbB Receptors / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000378:metabolism; D009077:Mucins / Q000096:biosynthesis*; D047495:PPAR gamma / Q000378:metabolism*; D016966:Porphyromonas gingivalis / Q000378:metabolism*; D051381:Rats; D012469:Salivary Glands / Q000187:drug effects / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology; D015533:Transcriptional Activation; D019061:src-Family Kinases / Q000378:metabolism*
D007004:Hypoglycemic Agents; D008070:Lipopolysaccharides; D009077:Mucins; D047495:PPAR gamma; D045162:Thiazolidinediones; D066246:ErbB Receptors; D019061:src-Family Kinases; C039671:ciglitazone