title: Inflammatory mediators alter interleukin-17 receptor, interleukin-12 and -23 expression in human osteoarthritic and rheumatoid arthritis synovial fibroblasts: immunomodulation by vasoactive intestinal Peptide.
abstract: OBJECTIVE
  To assess the contribution of fibroblast-like synoviocytes (FLS) to the inflammatory joint microenvironment under different pathogenic stimuli and their potential to respond to interleukin (IL)-17 and to determine whether the neuroimmunomodulatory vasoactive intestinal peptide (VIP) is able to modulate IL-17 receptor (IL-17R) and related cytokines.
  
  
  METHODS
  The effect of proinflammatory cytokines [tumor necrosis factor α (TNFα) and IL-17] and Toll-like receptor (TLR) ligands [poly(I:C) and lipopolysaccharide (LPS)] on IL-17R expression and IL-12 and IL-23 production was studied in osteoarthritis (OA)- and rheumatoid arthritis (RA)-FLS, involved in Th1/Th17 differentiation. The effect of VIP was also determined. IL-17RA, IL-17RC, IL-12p35 and IL-23p19 expression was measured by real-time polymerase chain reaction. IL-12 and IL-23 protein levels were measured by ELISA in supernatant cultures.
  
  
  RESULTS
  TNFα, LPS and poly(I:C) induced an increase in IL-17RA in RA-FLS, whereas TNFα, TNFα plus IL-17 and poly(I:C) enhanced IL-17RC transcripts in FLS. VIP diminished the upregulated expression of IL-17RA in RA-FLS following TNFα and poly(I:C). TNFα, LPS and poly(I:C) increased IL-12 and IL-23 levels in cells derived from patients presenting both pathologies. However, IL-17A DECREASED IL-12 AND AUGMENTED IL-23. VIP DECREASED IL-12P35 MRNA UPREGULATION BY POLY(I:C) AND IL-23P19 TRANSCRIPTS IN LPS-TREATED FLS.
  
  
  CONCLUSIONS
  Inflammatory cytokines and TLR ligands modulate IL-17R, IL-12 and IL-23 possibly favoring the cross talk between FLS and Th1/Th17 cells. The ability of VIP to counteract the enhancing effect of proinflammatory molecules on IL-17R and the IL-12 family of cytokines corroborates and amplifies the beneficial effect of this endogenous neuroimmunopeptide in rheumatic diseases.
authors.affiliation: Departamento de Biología Celular, Facultad de Biología, Universidad Complutense de Madrid, Madrid, Spain.
authors.forename: Mar
authors.initials: M
authors.lastname: Carrión
authors.forename: Selene
authors.initials: S
authors.lastname: Pérez-García
authors.forename: Rebeca
authors.initials: R
authors.lastname: Jimeno
authors.forename: Yasmina
authors.initials: Y
authors.lastname: Juarranz
authors.forename: Isidoro
authors.initials: I
authors.lastname: González-Álvaro
authors.forename: José Luis
authors.initials: JL
authors.lastname: Pablos
authors.forename: Irene
authors.initials: I
authors.lastname: Gutiérrez-Cañas
authors.forename: Rosa P
authors.initials: RP
authors.lastname: Gomariz
mesh_terms: D000704:Analysis of Variance; D001172:Arthritis, Rheumatoid / Q000473:pathology*; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism*; D053759:Interleukin-23 / Q000235:genetics / Q000378:metabolism*; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D010003:Osteoarthritis / Q000473:pathology*; D011089:Polydeoxyribonucleotides / Q000494:pharmacology; D012333:RNA, Messenger; D053722:Receptors, Interleukin-17 / Q000235:genetics / Q000378:metabolism*; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology
chemical_list: D016207:Cytokines; D053759:Interleukin-23; D008024:Ligands; D008070:Lipopolysaccharides; D011089:Polydeoxyribonucleotides; D012333:RNA, Messenger; D053722:Receptors, Interleukin-17; D018664:Interleukin-12; C031156:poly d(I-C); D014660:Vasoactive Intestinal Peptide