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

• Published in: The Journal of pharmacology and experimental therapeutics 2009-09, Vol.330 (3), p.756-763
• Main Authors: Dornelles, Fabiana N, Santos, Diógenes S, Van Dyke, Thomas E, Calixto, João B, Batista, Jr, Eraldo L, Campos, Maria M
• Format: Article
• Language: English
• Subjects: Animals; Anti-Inflammatory Agents - pharmacology; Antibodies, Monoclonal - pharmacology; Bradykinin - analogs & derivatives; Bradykinin - pharmacology; Dexamethasone - pharmacology; Edema - chemically induced; Edema - metabolism; Edema - pathology; Eicosapentaenoic Acid - analogs & derivatives; Eicosapentaenoic Acid - pharmacology; Foot - pathology; Infliximab; Lipopolysaccharides - pharmacology; Male; Neutrophil Infiltration - drug effects; Neutrophils - drug effects; Neutrophils - enzymology; Peroxidase - metabolism; Porphyromonas gingivalis - chemistry; Rats; Rats, Wistar; Receptor, Bradykinin B1 - biosynthesis; Receptor, Bradykinin B1 - drug effects; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; Up-Regulation - drug effects
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.109.155762

It has been demonstrated that kinin B 1 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 B 1 receptor up-regulation. In this study, we demonstrate that Pg-LPS injection into the rat paw resulted in a marked functional up-regulation of B 1 receptors (as measured by an increase of B 1 receptor-induced edema), which was preceded by a rapid rise in B 1 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 B 1 receptor induction. The functional and molecular Pg-LPS-elicited B 1 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 (5 S ,12 R ,18 R )-trihydroxy-6 Z ,8 E ,10 E ,14 Z ,16 E -eicosapentaenoic acid (resolvin E1; 300 ng/rat i.p.) was able to markedly down-regulate Pg-LPS-driven B 1 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 B 1 receptors through mechanisms involving TNF-α release and neutrophil influx, which are largely sensitive to resolvin E1. It is tempting to suggest that kinin B 1 receptors might well represent a pivotal pathway for the inflammatory responses evoked by P. gingivalis and its virulence factors.