In Vivo Up-Regulation of Kinin B₁ Receptors after Treatment with Porphyromonas gingivalis Lipopolysaccharide in Rat Paw

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.