Abstract
Disturbances in nitric oxide synthase (NOS) system and the excessive prostaglandin (PGE2) 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 PGE2 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 PGE2 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 PGE2 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.
Highlights
Porphyromonas gingivalis is a Gram-negative bacterium found in periodontal packets of patients with periodontitis, a chronic destructive inflammatory disease that is a major cause of adult tooth loss [1,2]
Our findings suggest that P. gingivalis-induced up-regulation in iNOS leads to COX-2 S-nitrosylation and up-regulation in PGE2 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
We found that the effect of P. gingivalis LPS on the acinar cell capacity for nitric oxide (NO) and PGE2 production was not appreciably influenced by COX-1 inhibition with SC-560, while preincubation with COX-2 inhibitor, NS-398, resulted in a marked reduction in PGE2 generation but had no discernible effect on the LPS-induced NO production (Figure 3)
Summary
Porphyromonas gingivalis is a Gram-negative bacterium found in periodontal packets of patients with periodontitis, a chronic destructive inflammatory disease that is a major cause of adult tooth loss [1,2]. Of the three NOS isozymes responsible for NO generation, the two expressed constitutively (cNOS) are membrane bound and Ca2+-dependent, and provide precise pulses of NO for a fine modulation of the cellular processes that are of importance to the maintenance of normal physiological functions [8,12, 14]. The COX-1 is responsible for maintaining the normal physiological prostaglandin production required for housekeeping functions, while the induction of COX-2 expression in response to inflammatory stimulus accounts for up-regulation in PGE2 production observed in various inflammatory diseases [8,11, 13,17]. The COX-2 activation and the resulting increase in PGE2 generation has been linked to the enzyme protein S-nitrosylation associated with LPS-induced up-regulation in iNOS expression [10,18]. Our results revealed that induction of iNOS by the LPS leads to COX-2 activation through S-nitrosylation, and that ghrelin-induced up-regulation in cNOS activation through phosphorylation results in the suppression of iNOS induction and prevents the COX-2 activation
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