Abstract
It has been demonstrated that kinin B1 receptors are highly up-regulated under several stressful stimuli, such as infection. However, there is no evidence indicating whether Porphyromonas gingivalis lipopolysaccharide (Pg-LPS) might lead to B1 receptor up-regulation. In this study, we demonstrate that Pg-LPS injection into the rat paw resulted in a marked functional up-regulation of B1 receptors (as measured by an increase of B1 receptor-induced edema), which was preceded by a rapid rise in B1 receptor mRNA expression. The local administration of Pg-LPS also resulted in a prominent production of the proinflammatory cytokine tumor necrosis factor α (TNF-α), followed by an increase of neutrophil influx; both events were observed at periods before B1 receptor induction. The functional and molecular Pg-LPS-elicited B1 receptor up-regulation was significantly reduced by the glucocorticoid dexamethasone (0.5 mg/kg s.c.), and to a lesser extent by the chimeric anti-TNF-α antibody infliximab (1 mg/kg s.c.). Of high relevance, we show for the first time that a single administration of the proresolution lipid mediator (5S,12R,18R)-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid (resolvin E1; 300 ng/rat i.p.) was able to markedly down-regulate Pg-LPS-driven B1 receptor expression, probably by inhibiting TNF-α production and neutrophil migration. Collectively, the present findings clearly suggest that Pg-LPS is able to induce the up-regulation of B1 receptors through mechanisms involving TNF-α release and neutrophil influx, which are largely sensitive to resolvin E1. It is tempting to suggest that kinin B1 receptors might well represent a pivotal pathway for the inflammatory responses evoked by P. gingivalis and its virulence factors.
Footnotes
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This work was supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (Brazil), Edital Universal [Grant 473012/2006-5].
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T.E.V.D. is named on patents awarded to Boston University that are subject to royalty payments.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.109.155762.
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ABBREVIATIONS: AUC, area under the time-response curve; BK, bradykinin; MPO, myeloperoxidase; LPS, lipopolysaccharide; Pg-LPS, Porphyromonas gingivalis LPS; PBS, phosphate-buffered saline; PCR, polymerase chain reaction; TLR, Toll-like receptor; TNF-α, tumor necrosis factor α; ELISA, enzyme-linked immunosorbent assay; resolvin E1, RvE1, (5S,12R,18R)-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid.
- Received May 3, 2009.
- Accepted June 24, 2009.
- The American Society for Pharmacology and Experimental Therapeutics
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