title: Differential expression of vasoactive intestinal peptide and its functional receptors in human osteoarthritic and rheumatoid synovial fibroblasts.
abstract: OBJECTIVE
  Vasoactive intestinal peptide (VIP) has shown potent antiinflammatory effects in murine arthritis and ex vivo in human rheumatoid arthritis (RA) synovial cells. To investigate the potential endogenous participation of this system in the pathogenesis of RA, we analyzed the expression and regulation of VIP and its functional receptors in human fibroblast-like synoviocytes (FLS) from patients with osteoarthritis (OA) and patients with RA.
  
  
  METHODS
  The expression of VIP was studied by reverse transcription-polymerase chain reaction (RT-PCR), enzyme immunoassay, and immunofluorescence in cultured FLS, and by immunohistochemical analysis in synovial tissue. The expression and function of the potential VIP receptors in FLS were studied by RT-PCR, determination of intracellular cAMP production, cell membrane adenylate cyclase (AC) activity, and interleukin-6, CCL2, and CXCL8 production in response to VIP or specific agonists and antagonists.
  
  
  RESULTS
  VIP expression was detected in human FLS at the messenger RNA and protein levels, and it was significantly decreased in RA FLS compared with OA FLS. VIP receptor type 1 (VPAC1) was the dominant AC-coupled receptor in OA FLS, in contrast with RA FLS, in which VPAC2 was dominant. Tumor necrosis factor alpha-treated OA FLS reproduced the VIP and VPAC receptor expression pattern of RA FLS. The antagonistic effects of VIP on FLS proinflammatory factor production were reproduced by VPAC1- and VPAC2-specific agonists in OA FLS and RA FLS, respectively.
  
  
  CONCLUSIONS
  VIP expression is down-regulated in RA and in tumor necrosis factor alpha-treated FLS, suggesting that down-regulation of this endogenous antiinflammatory factor may contribute to the pathogenesis of RA. In RA FLS, VPAC2 mediates the antiinflammatory effects of VIP, suggesting that VPAC2 agonists may be an alternative to VIP as antiinflammatory agents.
authors.affiliation: Departamento de Biología Celular, Facultad de Biología, Universidad Complutense de Madrid, Madrid, Spain. yashina@bio.ucm.es
authors.forename: Yasmina
authors.initials: Y
authors.lastname: Juarranz
authors.forename: Irene
authors.initials: I
authors.lastname: Gutiérrez-Cañas
authors.forename: Begoña
authors.initials: B
authors.lastname: Santiago
authors.forename: Mar
authors.initials: M
authors.lastname: Carrión
authors.forename: José L
authors.initials: JL
authors.lastname: Pablos
authors.forename: Rosa P
authors.initials: RP
authors.lastname: Gomariz
mesh_terms: D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000503:physiopathology; D002478:Cells, Cultured; D015536:Down-Regulation; D005347:Fibroblasts / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D020370:Osteoarthritis, Knee / Q000378:metabolism* / Q000503:physiopathology; D051239:Receptors, Vasoactive Intestinal Peptide, Type II / Q000819:agonists / Q000378:metabolism; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I / Q000819:agonists / Q000378:metabolism; D013583:Synovial Membrane / Q000166:cytology / Q000378:metabolism* / Q000503:physiopathology; D014660:Vasoactive Intestinal Peptide / Q000378:metabolism*
chemical_list: D051239:Receptors, Vasoactive Intestinal Peptide, Type II; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; C495506:VIPR1 protein, human; C495509:VIPR2 protein, human; D014660:Vasoactive Intestinal Peptide