Protease-activated receptor-2 activation: a major role in the pathogenesis of Porphyromonas gingivalis infection.
We have investigated the specific contribution of protease-activated receptor-2 (PAR(2)) to host defense during Porphyromonas gingivalis infection. Culture supernatants from P. gingivalis strains 33277 and W50 provoked Ca(2+) mobilization in cells transfected with PAR(2) (PAR(2)-KNRK) and desensitized the subsequent responses to PAR(2)-selective agonist. In addition, culture supernatants of P. gingivalis E8 (RgpA/RgpB double knockout) did not cause calcium response in PAR(2)-KNRK cells, evidencing the involvement of the arginine-specific cysteine proteases RgpA and RgpB in PAR(2) activation by P. gingivalis. Injection of P. gingivalis into mouse subcutaneous chambers provoked an increased proteolytic activity, which was inhibited by serine protease inhibitors. Fluids collected from chambers of P. gingivalis-injected mice were able to activate PAR(2) and this activation was inhibited by serine protease inhibitors. P. gingivalis inoculation into subcutaneous chambers of wild-type mice induced an inflammatory response that was inhibited by a serine protease inhibitor and was significantly reduced in PAR(2)-deficient mice. Finally, mice orally challenged with P. gingivalis developed alveolar bone loss, which was significantly reduced in PAR(2)-deficient mice at 42 and 60 days after P. gingivalis infection. We conclude that PAR(2) is activated on P. gingivalis infection, in which it plays an important role in the host inflammatory response.
Holzhausen
Marinella
M
Pharmacology and Therapeutics, Faculty of Medicine, University of Calgary, 3330 Hospital Dr., NW Calgary, T2N 4N1 Alberta, Canada.
Spolidorio
Luis Carlos
LC
Ellen
Richard P
RP
Jobin
Marie-Claude
MC
Steinhoff
Martin
M
Andrade-Gordon
Patricia
P
Vergnolle
Nathalie
N
D018829:Adhesins, Bacterial / Q000378:metabolism; D016301:Alveolar Bone Loss / Q000382:microbiology; D000818:Animals; D016866:Bacteroidaceae Infections / Q000378:metabolism* / Q000382:microbiology; D020013:Calcium Signaling; D003546:Cysteine Endopeptidases / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D000080867:Gingipain Cysteine Endopeptidases; D051379:Mice; D018345:Mice, Knockout; D010447:Peptide Hydrolases / Q000378:metabolism; D010518:Periodontitis / Q000378:metabolism* / Q000382:microbiology; D016966:Porphyromonas gingivalis / Q000472:pathogenicity*; D044464:Receptor, PAR-2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D018829:Adhesins, Bacterial; D016207:Cytokines; D000080867:Gingipain Cysteine Endopeptidases; D044464:Receptor, PAR-2; D010447:Peptide Hydrolases; D003546:Cysteine Endopeptidases; D015232:Dinoprostone