Proinflammatory role of proteinase-activated receptor-2 in humans and mice during cutaneous inflammation in vivo.
Proteinase-activated receptor-2 belongs to a new subfamily of G-protein-coupled receptors. Its precise role during inflammation and the underlying mechanisms is still unclear. Our study establishes that PAR-2 plays a direct proinflammatory role during cutaneous inflammation in mice and humans in vivo. In a model of experimentally induced allergic (ACD) and toxic (ICD) contact dermatitis (CD) we show that ear swelling responses, plasma extravasation, and leucocyte adherence were significantly attenuated in PAR-2 null mutant (PAR-2-/-) mice compared with wild-type (PAR-2+/+) mice, especially at early stages. The proinflammatory effects by PAR-2 activation were significantly diminished using nitric oxide-synthase inhibitors, while NF-kappaB and neuropeptides appear to play a minor role in these mechanisms. PAR-2-mediated up-regulation of E-selectin and cell adhesion molecule ICAM-1; enhanced plasma extravasation was observed in humans and mice and of interleukin-6 in mice in vivo. Thus, PAR-2 may be a beneficial therapeutic target for the treatment of inflammatory skin diseases.
D000293:Adolescent; D000328:Adult; D000818:Animals; D002199:Capillary Permeability; D002448:Cell Adhesion; D003872:Dermatitis / Q000276:immunology*; D017449:Dermatitis, Allergic Contact / Q000276:immunology; D003877:Dermatitis, Contact / Q000276:immunology / Q000473:pathology; D020405:Dermis / Q000473:pathology; D019040:E-Selectin / Q000378:metabolism; D004487:Edema / Q000209:etiology / Q000473:pathology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007962:Leukocytes / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009569:Nitric Oxide / Q000502:physiology; D009842:Oligopeptides / Q000494:pharmacology; D044464:Receptor, PAR-2; D018179:Receptors, Thrombin / Q000819:agonists / Q000502:physiology*; D012867:Skin / Q000098:blood supply / Q000187:drug effects / Q000276:immunology; D015854:Up-Regulation
D019040:E-Selectin; D009842:Oligopeptides; D044464:Receptor, PAR-2; D018179:Receptors, Thrombin; C109968:seryl-leucyl-isoleucyl--glycyl-lysyl-valine; D018799:Intercellular Adhesion Molecule-1; D009569:Nitric Oxide