title: Immunomodulatory role of proteinase-activated receptor-2.
abstract: OBJECTIVE
  Proteinase-activated receptor-2 (PAR(2)) has been implicated in inflammatory articular pathology. Using the collagen-induced arthritis model (CIA) the authors have explored the capacity of PAR(2) to regulate adaptive immune pathways that could promote autoimmune mediated articular damage.
  
  
  METHODS
  Using PAR(2) gene deletion and other approaches to inhibit or prevent PAR(2) activation, the development and progression of CIA were assessed via clinical and histological scores together with ex vivo immune analyses.
  
  
  RESULTS
  The progression of CIA, assessed by arthritic score and histological assessment of joint damage, was significantly (p<0.0001) abrogated in PAR(2) deficient mice or in wild-type mice administered either a PAR(2) antagonist (ENMD-1068) or a PAR(2) neutralising antibody (SAM11). Lymph node derived cell suspensions from PAR(2) deficient mice were found to produce significantly less interleukin (IL)-17 and IFNγ in ex vivo recall collagen stimulation assays compared with wild-type littermates. In addition, substantial inhibition of TNFα, IL-6, IL-1β and IL-12 along with GM-CSF and MIP-1α was observed. However, spleen and lymph node histology did not differ between groups nor was any difference detected in draining lymph node cell subsets. Anticollagen antibody titres were significantly lower in PAR(2) deficient mice.
  
  
  CONCLUSIONS
  These data support an important role for PAR(2) in the pathogenesis of CIA and suggest an immunomodulatory role for this receptor in an adaptive model of inflammatory arthritis. PAR(2) antagonism may offer future potential for the management of inflammatory arthritides in which a proteinase rich environment prevails.
authors.affiliation: School of Science, University of the West of Scotland, Paisley PA1 2BE, Scotland, UK. Anne.Crilly@glasgow.ac.uk
authors.forename: Anne
authors.initials: A
authors.lastname: Crilly
authors.forename: Helen
authors.initials: H
authors.lastname: Palmer
authors.forename: Mohammad B
authors.initials: MB
authors.lastname: Nickdel
authors.forename: Lynette
authors.initials: L
authors.lastname: Dunning
authors.forename: John C
authors.initials: JC
authors.lastname: Lockhart
authors.forename: Robin
authors.initials: R
authors.lastname: Plevin
authors.forename: Iain B
authors.initials: IB
authors.lastname: McInnes
authors.forename: William R
authors.initials: WR
authors.lastname: Ferrell
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology; D005434:Flow Cytometry; D007155:Immunologic Factors / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D044464:Receptor, PAR-2 / Q000276:immunology / Q000378:metabolism*
chemical_list: D007155:Immunologic Factors; D044464:Receptor, PAR-2