title: Genetic association of vasoactive intestinal peptide receptor with rheumatoid arthritis: altered expression and signal in immune cells.
abstract: OBJECTIVE
  Vasoactive intestinal peptide (VIP) has been shown to be one of the endogenous factors involved in the maintenance of immune tolerance. Administration of VIP ameliorates clinical signs in various experimental autoimmune disorders. This study was undertaken to investigate whether the exacerbated inflammatory autoimmune response in rheumatoid arthritis (RA) might result directly from altered expression and/or signaling of VIP receptors in immune cells.
  
  
  METHODS
  The effect of specific agonists of different VIP receptors on collagen-induced arthritis in mice was investigated by clinical and histologic assessment and measurement of cytokine and chemokine production. Expression of VIP receptor type 1 (VPAC1) in synovial cells and monocytes from RA patients was determined by flow cytometry. Potential associations of VPAC1 genetic polymorphisms with RA susceptibility were investigated.
  
  
  RESULTS
  A VPAC1 agonist was very efficient in the treatment of experimental arthritis, and deficient expression of VPAC1 in immune cells of RA patients was associated with the predominant proinflammatory Th1 milieu found in this disease. Immune cells derived from RA patients were less responsive to VIP signaling than were cells from healthy individuals and showed reduced VIP-mediated immunosuppressive activity, rendering leukocytes and synovial cells more proinflammatory in RA. A significant association between multiple-marker haplotypes of VPAC1 and susceptibility to RA was found, suggesting that the reduced VPAC1 expression in RA-derived immune cells is associated with the described VPAC1 genetic polymorphism.
  
  
  CONCLUSIONS
  These findings are highly relevant to the understanding of RA pathogenesis. They suggest that VIP signaling through VPAC1 is critical to maintaining immune tolerance in RA. In addition, the results indicate that VPAC1 may be a novel therapeutic target in RA.
authors.affiliation: Instituto de Parasitología y Biomedicina López Neyra, CSIC, Granada, Spain. mdelgado@ipb.csic.es
authors.forename: Mario
authors.initials: M
authors.lastname: Delgado
authors.forename: Gema
authors.initials: G
authors.lastname: Robledo
authors.forename: Blanca
authors.initials: B
authors.lastname: Rueda
authors.forename: Nieves
authors.initials: N
authors.lastname: Varela
authors.forename: Francisco
authors.initials: F
authors.lastname: O'Valle
authors.forename: Pedro
authors.initials: P
authors.lastname: Hernandez-Cortes
authors.forename: Marta
authors.initials: M
authors.lastname: Caro
authors.forename: Gisela
authors.initials: G
authors.lastname: Orozco
authors.forename: Elena
authors.initials: E
authors.lastname: Gonzalez-Rey
authors.forename: Javier
authors.initials: J
authors.lastname: Martin
mesh_terms: D000328:Adult; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000503:physiopathology; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D051239:Receptors, Vasoactive Intestinal Peptide, Type II / Q000819:agonists / Q000378:metabolism; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I / Q000819:agonists / Q000378:metabolism*; D014660:Vasoactive Intestinal Peptide / Q000276:immunology*
chemical_list: D051239:Receptors, Vasoactive Intestinal Peptide, Type II; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; C495506:VIPR1 protein, human; C495509:VIPR2 protein, human; C495507:Vipr1 protein, mouse; C495510:Vipr2 protein, mouse; D014660:Vasoactive Intestinal Peptide