OBJECTIVES: 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. CONCLUSION: 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.

Department of Dermatology and Venereology 1st Faculty of Medicine Charles University Prague and General University Hospital Prague Prague Czech Republic

Department of Internal Medicine 3 and Institute for Clinical Immunology University of Erlangen Nuremberg Erlangen Germany

Institute of Rheumatology and Department of Rheumatology of the 1st Faculty of Medicine Charles University Prague Prague Czech Republic

Institute of Rheumatology and Department of Rheumatology of the 1st Faculty of Medicine Charles University Prague Prague Czech Republic Department of Internal Medicine 3 and Institute for Clinical Immunology University of Erlangen Nuremberg Erlangen Germany

Institute of Rheumatology and Department of Rheumatology of the 1st Faculty of Medicine Charles University Prague Prague Czech Republic Faculty of Physical Education and Sport Charles University Prague and

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