Elevated serum interleukin-35 is associated with disease activity in patients with systemic lupus erythematosus.

Abstract

Dear Editor, Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with a wide variety of presenting features. Many studies have suggested cytokines are involved in the pathogenesis of SLE.1-4 Interleukin (IL)-35, a heterodimeric cytokine composed of the subunits EBI3 and p35, was recently identified as a new member of the IL-12 cytokine family.5 The role of IL-35 remains controversial in inflammatory diseases. Some studies have shown its anti-inflammatory properties given its effect on Treg, regulator B cells and associated cytokines in inflammatory bowel disease, collagen-induced arthritis or other autoimmune diseases.6-8 In contrast, IL-35 enhanced the inflammatory response in Lyme arthritis9 and IL-35 gene therapy exacerbates experimental rheumatoid arthritis in mice.10 The expression and significance of IL-35 in patients with SLE is still obscure. Several studies have shown that the level of IL-35 was decreased and the percentage of CD4+ EBI3+ T cells were also significantly decreased in patients with active SLE.11, 12 Another study showed that plasma IL-35 and soluble gp130 levels were significantly higher in patients with severe SLE.13 We conducted this study to investigate the IL-35 level in patients with SLE and their potential association with clinical manifestations and disease activity. We enrolled 145 patients with SLE (133 females and 12 males, mean age 35.6 ± 13.9 years) and 69 age- and sex-matched healthy volunteers without diseases. The protocol for the study was approved by the Ethics Committee of Peking University People's Hospital (FWA00001384). Clinical and laboratory features of SLE patients were recorded. Serum levels of IL-35 were measured by enzyme-linked immunosorbent assay according to the manufacturer's protocol (USCN Life Science, Wuhan, China). The levels of serum IL-35 were significantly higher in patients with SLE than in healthy controls (125.7 ± 110.5 vs. 19.1 ± 45.4, t = 10.050, P = 0.0000) (Fig. 1). The levels of IL-35 were significantly higher in SLE patients with SLE Disease Activity Index (SLEDAI) scores ≥ 8 than patients with SLEDAI score < 8 (85.29 vs. 54.57, Z = −4.314, P = 0.000). The levels of serum IL-35 were correlated with anti-double-stranded DNA antibodies (r = 0.214, P = 0.010) and SLEDAI scores(r = 0.326, P = 0.000) (Fig. 2). The levels of serum IL-35 decreased significantly in accordance with disease activity after treatment in a subgroup of 19 patients with SLE (Fig. 3). Serum levels of IL-35 were associated with photosensitivity (115.5 ± 96.2 vs. 194.1 ± 170.5, t = −2.945, P = 0.004), arthritis (109.8 ± 104.5 vs. 161.4 ± 118.5, t = −2.636, P = 0.009) and fever (109.3 ± 103.9 vs. 161.3 ± 119.1, t = −2.672, P = 0.008) (Table 1). We could see that IL-35 levels were lower in SLE patients with antiphospholipid syndrome (APS) than those without APS, but there was no statistical difference between these two groups. In conclusion, we demonstrate circulating IL-35 is significantly higher than healthy controls and associate with disease activity in SLE. IL-35 might be involved in the pathogenesis of SLE. This work was supported by the National Nature Science Foundation of China (grant no. NSFC.81202297). The authors have no conflicts of interest to declare.