title: Protease-activated receptor 2 mediates the proinflammatory effects of synovial mast cells.
abstract: OBJECTIVE
  Mast cells are hypothesized to play a role in the pathogenesis of rheumatoid arthritis (RA) by mechanisms requiring elucidation. Tryptase released from these cells can activate protease-activated receptor 2 (PAR-2), which was recently shown to have proinflammatory actions. The purpose of this study was to examine the relationship between synovial mast cells and PAR-2. Mast cell proximity to PAR-2-expressing cells was investigated in RA synovium. In murine studies, we assessed the capacity of mast cell tryptase to mediate synovial proinflammatory responses via PAR-2 and whether degranulating mast cells induced synovial hyperemia by PAR-2 activation.
  
  
  METHODS
  RA synovial tissue was examined by immunohistochemistry. PAR-2(+/+) and PAR-2(-/-) C57BL/6J mice were used to investigate the PAR-2 dependence of compound 48/80-induced synovial hyperemia, as measured by laser Doppler imaging, and joint swelling and hyperemic responses to recombinant human beta-tryptase.
  
  
  RESULTS
  Mast cells and synovial lining cells staining for PAR-2 were colocalized in RA articular tissue. Compound 48/80 administration resulted in vasodilatation in PAR-2(+/+) mice but not in PAR-2(-/-) mice, which showed a vasoconstrictor response. Eliminating the 5-hydroxytryptamine-mediated component of this response with methysergide unveiled an enhanced PAR-2-mediated vasodilatation to compound 48/80 in PAR-2(+/+) mice and ablated the vasoconstrictor response in PAR-2(-/-) mice. Treatment with beta-tryptase resulted in dose-dependent knee joint swelling and synovial vasodilatation in PAR-2(+/+) mice but not PAR-2(-/-) mice.
  
  
  CONCLUSIONS
  This in vivo study is the first to explore the relationship between synovial mast cells and PAR-2. Our results support the hypothesis that mast cells contribute to the pathogenesis of inflammatory arthritis through PAR-2 activation via release of mast cell tryptase.
authors.affiliation: University of Paisley, Paisley, UK.
authors.forename: H S
authors.initials: HS
authors.lastname: Palmer
authors.forename: E B
authors.initials: EB
authors.lastname: Kelso
authors.forename: J C
authors.initials: JC
authors.lastname: Lockhart
authors.forename: C P
authors.initials: CP
authors.lastname: Sommerhoff
authors.forename: R
authors.initials: R
authors.lastname: Plevin
authors.forename: F G
authors.initials: FG
authors.lastname: Goh
authors.forename: W R
authors.initials: WR
authors.lastname: Ferrell
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015550:Cell Degranulation / Q000276:immunology; D004487:Edema / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006940:Hyperemia / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D007719:Knee Joint / Q000098:blood supply / Q000276:immunology / Q000473:pathology; D017078:Laser-Doppler Flowmetry; D008407:Mast Cells / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D044464:Receptor, PAR-2 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D013583:Synovial Membrane / Q000276:immunology* / Q000473:pathology; D053802:Tryptases / Q000378:metabolism
chemical_list: D044464:Receptor, PAR-2; D053802:Tryptases