Cyclooxygenase-2 S-nitrosylation in salivary gland acinar cell inflammatory responses to <i>Porphyromonas gingivalis</i>: modulatory effect of ghrelin

Abstract

Disturbances in nitric oxide synthase (NOS) system and the excessive prostaglandin (PGE 2 ) generation are well-recognized features of oral mucosal inflammatory responses to periodontopathic bacterium, P. gingivalis. Employing rat sublingual gland acinar cells, we show that P. gingivalis LPS-induced up-regulation in PGE 2 generation and the enhancement in inducible (i) iNOS activity was associated with COX-2 activation through S-nitrosylation, and accompanied by the suppression in cSrc activity and the impairment in constitutive (c) cNOS phosphorylation. Further, we demonstrate that the countering effect of peptide hormone, ghrelin, on the LPS-induced changes was reflected in the increased cNOS activation through phosphorylation, repression in iNOS induction, and the reduction in PGE 2 generation associated with the loss of COX-2 protein S-nitrosylation. Moreover, the effect of ghrelin on cNOS phosphorylation and the LPS-induced COX-2 S-nitrosylation was susceptible to the blockage by cSrc inhibition. Our findings suggest that P. gingivalis-induced up-regulation in iNOS leads to COX-2 S-nitrosylation and up-regulation in PGE 2 generation, and that the countering effect of ghrelin is mediated through Src-dependent cNOS activation that is obligatory for the maintenance of iNOS gene suppression.

Proinflammatory Signaling Cascades of Periodontopathic Oral Pathogen <i>Porphyromonas gingivalis</i>

“…characterized by a massive rise in epithelial cell apoptosis and proinflammatory cytokine expression, excessive NO generation, and a marked increase in PGE2 production[22] [28] [58]. A growing volume of literature, moreover, points towards the existence of functional and signaling relationship between NO, generated by the action of NOS, and the formation of PGE2 synthesized from arachidonic acid (AA) by the action of COX systems[30] [59] [60]. While NO and PGE2 generated by the constitutive nitric oxide synthase (cNOS) and cyclooxygenase-1 (COX-1) enzyme systems are deemed essential to maintaining normal housekeeping functions, the induction of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression in response to inflammatory stimulus, including that of P. gingivalis LPS, have been demonstrated to promote the proinflammatory events propagation [37] [59] [61].…”

“…This results in the repression of iNOS gene induction and the inhibition of COX-2 activation through iNOS-dependent S-nitrosylation, as well as the suppression of AA release. activation through S-nitrosylation that results in an excessive PGE2 generation[30].…”