Background IL-35, a dimeric protein with two subunits, IL-12A (p35) and Epstein-Barr virus induced 3, is a novel IL-12 cytokine family regulatory T-cells (Treg)-specific immunosuppressive/anti-inflammatory cytokine. IL-35 is expressed by resting and activated regulatory T cells (Tregs/Tr35) by converting conventional T cells (Tconv) into IL-35-dependent induced Tregs (iTr35), but not effector T cells. Similar to that of transforming growth factor (TGF-β) and IL-10, IL-35 is the major component of the suppressive repertoire, but temporally different from them in the inhibition of inflammation.
Objectives Since there are little studies for the regulatory roles of IL-35 on the activation of systemic lupus erythematous (SLE), we hypothesize that IL-35 may play an important immunoregulatory roles in SLE.
Methods Recruited subjects were classified into 4 groups based on the SLE disease activity index (SLEDAI): mild SLE (SLEDAI<4), moderate SLE (4≤SLEDAI<8), severe SLE (SLEDAI≥8), and healthy controls (HC). Plasma concentrations of IL-35 and soluble gp130 were measured using ELISA. Production of IL-35 receptor subunits IL-12Rβ2 and gp130 on the CD4+ helper (Th) cells and CD19+ B cells, and the number of CD4+CD25highCD127– Treg cells were quantitated by flow cytometry. The ex vivo effect of IL-35 on the lymphocyte produced cytokines were measured using luminex multiplex assay. The mRNA expression level was detected by RT-qPCR.
Results Plasma IL-35 and soluble gp130 levels positively correlated with each other and both were significantly higher in severe SLE patients than HC. In addition, the ex vivo production of proinflammatory cytokines CXCL8, CCL2, IFN-γ and IL-17A were significantly lower in severe SLE patients, but the ex vivo production of anti-inflammatory cytokine TGF-β was elevated in severe SLE patients. Consistent with the expression of gp130 on Th cells, the percentages of Tregs in severe and moderate SLE patients were both significantly lower than HC. Moreover, the gp130 expression and Tregs proportion were positively correlated each other, and both of them were negatively correlated with SLEDAI (all p<0.05). The mRNA expression levels of IL-35, IL-35 receptor and Foxp3 in patients with SLE were not only significantly higher than HC, but also positively correlated with each other and SLEDAI (all p<0.05).
Conclusions The above results may imply the potential immunoregulatory roles of IL-35 and its receptor. We assumed that TGF-β might associate with IL-35 to down-regulate the production of proinflammatory cytokines and expand the immunoregulatory function of IL-35 in autoimmune disease. The results of this cross-sectional clinical study may also furnish a potential therapeutic target of IL-35 for the treatment of autoimmune disease.
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Acknowledgements This study was supported by Direct Grant of Research (2012.2.010), The Chinese University of Hong Kong and National Natural Science Foundation of China (Grant No.: 81273248).
Disclosure of Interest : Z. Cai Employee of: No conflict of interest, C. Wong Consultant for: No conflict of interest, L. TAM Consultant for: No conflict of interest, Paid instructor for: No conflict of interest