title: Interleukin-35 is upregulated in systemic sclerosis and its serum levels are associated with early disease.
abstract: OBJECTIVE
  IL-35 is a member of the IL-12 family consisting of p35/IL-12a and EBI3/IL-27b subunits. IL-35 exerts immunomodulatory activities in experimental and human autoimmune inflammatory conditions. Our aim was to assess IL-35 expression in the skin and circulation of SSc patients and to characterize its potential association with SSc-related features.
  
  
  METHODS
  Expression of IL-35 in skin and dermal fibroblasts was quantified by quantitative PCR, immunohistochemistry and immunofluorescence. Serum levels of IL-35 (by ELISA), CRP (by turbidimetry), ANA (by immunofluorescence) and autoantibodies of the ENA complex (by immunoblot) were measured in 40 SSc patients. Serum IL-35 was determined in 40 age- and sex-matched healthy controls.
  
  
  RESULTS
  IL-35 expression was increased in SSc skin and dermal fibroblasts in a TGF-β-dependent manner. IL-35 induced an activated phenotype in resting fibroblasts and enhanced the release of collagen. IL-35 serum levels were increased in patients with SSc compared with healthy controls [median 83.9 (interquartile range 45.1-146.1) vs 36.2 (interquartile range 17.2-49.4) pg/ml, P < 0.0001]. Serum IL-35 was negatively correlated with disease duration (r = -0.4339, P = 0.0052). In line with this finding, serum IL-35 was increased in patients with an early SSc pattern on capillaroscopy assessment compared with those with active and late SSc patterns.
  
  
  CONCLUSIONS
  The present study demonstrates overexpression of IL-35 in SSc skin, dermal fibroblasts and serum. TGF-β induces IL-35, which in turn activates resting fibroblasts and enhances the release of collagen, thereby contributing to aberrant TGF-β signalling in SSc. Increased serum IL-35 is associated with early, inflammatory stages of SSc.
authors.affiliation: Institute of Rheumatology and Department of Rheumatology of the First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic, Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany, tomcik@revma.cz.
authors.forename: Michal
authors.initials: M
authors.lastname: Tomcik
authors.affiliation: Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Pawel
authors.initials: P
authors.lastname: Zerr
authors.affiliation: Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Palumbo-Zerr
authors.affiliation: Institute of Rheumatology and Department of Rheumatology of the First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
authors.forename: Hana
authors.initials: H
authors.lastname: Storkanova
authors.affiliation: Institute of Rheumatology and Department of Rheumatology of the First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
authors.forename: Hana
authors.initials: H
authors.lastname: Hulejova
authors.affiliation: Institute of Rheumatology and Department of Rheumatology of the First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic, Faculty of Physical Education and Sport, Charles University in Prague and.
authors.forename: Maja
authors.initials: M
authors.lastname: Spiritovic
authors.affiliation: Department of Dermatology and Venereology, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic.
authors.forename: Ondrej
authors.initials: O
authors.lastname: Kodet
authors.affiliation: Department of Dermatology and Venereology, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic.
authors.forename: Jiri
authors.initials: J
authors.lastname: Stork
authors.affiliation: Institute of Rheumatology and Department of Rheumatology of the First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
authors.forename: Radim
authors.initials: R
authors.lastname: Becvar
authors.affiliation: Institute of Rheumatology and Department of Rheumatology of the First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
authors.forename: Jiri
authors.initials: J
authors.lastname: Vencovsky
authors.affiliation: Institute of Rheumatology and Department of Rheumatology of the First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
authors.forename: Karel
authors.initials: K
authors.lastname: Pavelka
authors.affiliation: Institute of Rheumatology and Department of Rheumatology of the First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
authors.forename: Maria
authors.initials: M
authors.lastname: Filkova
authors.affiliation: Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Jörg H W
authors.initials: JH
authors.lastname: Distler
authors.affiliation: Institute of Rheumatology and Department of Rheumatology of the First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
authors.forename: Ladislav
authors.initials: L
authors.lastname: Senolt
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis; D005260:Female; D005347:Fibroblasts / Q000276:immunology; D006801:Humans; D007378:Interleukins / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics; D012595:Scleroderma, Systemic / Q000276:immunology*; D012867:Skin / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology
chemical_list: D007378:Interleukins; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; C532417:interleukin-35, human; D003094:Collagen
keywords: TGF-β; capillaroscopy; disease duration; interleukin-35; systemic sclerosis