title: Pro-inflammatory effects of interleukin-35 in rheumatoid arthritis.
abstract: OBJECTIVE
  Interleukin-35 (IL-35) is a heterodimeric member of the IL-12 family consisting of p35/IL-12a and EBI3/IL-27b subunits. Expressed in murine Treg cells, IL-35 controls inflammatory diseases in mouse models. However, human IL-35 is expressed in Teff cells rather than in Treg cells and is shown to be upregulated under inflammatory conditions. Our aim was to examine the involvement of IL-35 in the pathogenesis of rheumatoid arthritis (RA).
  
  
  METHODS
  Immunohistochemical and immunofluorescence analysis was used to determine the expression and localization of IL-35 and its subunits (p35/EBI3) and IL-35 receptor (IL12Rβ2/gp130) in RA, osteoarthritis (OA) and psoriatic arthritis (PsA) synovial tissues. Expression of p35/EBI3 subunits and release of inflammatory cytokines upon stimulation with IL-35 were assessed in RA synovial fibroblasts (SFs) and peripheral blood mononuclear cells (PBMCs).
  
  
  RESULTS
  Both IL-35 and its subunits were upregulated in RA in comparison with OA or PsA synovium. Using cell-specific markers, p35 and EBI3 were identified in macrophages, dendritic cells, SFs, and T as well as B cells in RA synovium. Both p35 and EBI3 were induced by TNFα in RASFs and PBMCs. IL-35 dose-dependently upregulated release of pro-inflammatory mediators IL-1β, IL-6 and MCP-1 in PBMCs. While gp130 receptor subunit was upregulated in RA synovium and was expressed in RASFs and PBMCs, there was no difference in IL12Rβ2 expression subunit among tissues and its presence in RASFs was lacking.
  
  
  CONCLUSIONS
  Upregulation of IL-35 at sites of inflammation in RA and its pro-inflammatory potential suggests that IL-35 might play an important role in RA pathogenesis.
authors.affiliation: Institute of Rheumatology, Prague, Czech Republic. Electronic address: MariaFilkova@seznam.cz.
authors.forename: Mária
authors.initials: M
authors.lastname: Filková
authors.affiliation: Institute of Pathology of the 3rd Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
authors.forename: Zdenka
authors.initials: Z
authors.lastname: Vernerová
authors.affiliation: Institute of Rheumatology, Prague, Czech Republic.
authors.forename: Hana
authors.initials: H
authors.lastname: Hulejová
authors.affiliation: Institute of Rheumatology, Prague, Czech Republic.
authors.forename: Klára
authors.initials: K
authors.lastname: Prajzlerová
authors.affiliation: 1st Orthopedic Clinic, 1st Faculty of Medicine and Faculty Hospital Motol, Charles University in Prague, Prague, Czech Republic.
authors.forename: David
authors.initials: D
authors.lastname: Veigl
authors.affiliation: Institute of Rheumatology, Prague, Czech Republic; Department of Rheumatology, 1st Faculty of Medicine, Charles University in Prague, Czech Republic.
authors.forename: Karel
authors.initials: K
authors.lastname: Pavelka
authors.affiliation: Institute of Rheumatology, Prague, Czech Republic; Department of Rheumatology, 1st Faculty of Medicine, Charles University in Prague, Czech Republic.
authors.forename: Jiří
authors.initials: J
authors.lastname: Vencovský
authors.affiliation: Institute of Rheumatology, Prague, Czech Republic; Department of Rheumatology, 1st Faculty of Medicine, Charles University in Prague, Czech Republic.
authors.forename: Ladislav
authors.initials: L
authors.lastname: Šenolt
mesh_terms: D000818:Animals; D015535:Arthritis, Psoriatic / Q000378:metabolism / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D007378:Interleukins / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D015778:Minor Histocompatibility Antigens; D021122:Protein Subunits / Q000378:metabolism; D013583:Synovial Membrane / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: C097732:EBI3 protein, human; D018836:Inflammation Mediators; D007378:Interleukins; D015778:Minor Histocompatibility Antigens; D021122:Protein Subunits; D014409:Tumor Necrosis Factor-alpha; C532417:interleukin-35, human
keywords: Inflammation; Interleukin-35; Rheumatoid arthritis; Synovial tissue