Interleukin-37 is increased in adult-onset Still\u2019s disease and associated with disease activity

Huihui Chi,Yufeng Yin,Xiaobing Cheng,Mengru Liu,Jialin Teng,Chengde Yang,Dongzhou Liu,Junna Ye,Xinyao Wu,Zhuochao Zhou,Hui Shi,Yutong Su,Qiongyi Hu,Honglei Liu,Yue Sun

doi:10.1186/s13075-018-1555-6

Abstract

BackgroundInterleukin (IL)-37 has been known to play an immunosuppressive role in various inflammatory disorders, but whether it participates in the regulation of pathogenesis of adult-onset Still’s disease (AOSD) has not been investigated. In this study, we examined serum IL-37 levels and their clinical association with AOSD, and we explored the anti-inflammatory effects of IL-37 on peripheral blood mononuclear cells (PBMCs) from patients with AOSD.MethodsBlood samples were collected from 62 patients with AOSD and 50 healthy control subjects (HC). The serum IL-37 levels were determined using an enzyme-linked immunosorbent assay (ELISA). The correlations of serum IL-37 levels with disease activity, laboratory values, and inflammatory cytokines in AOSD were analyzed by Spearman’s correlation test. The correlations between serum IL-37 levels and clinical manifestations were analyzed by Mann-Whitney U test. PBMCs from ten patients with AOSD were stimulated with recombinant human IL-37 protein, and expression levels of tumor necrosis factor (TNF)-α, IL-6, IL-10, IL-1β, and IL-18 were determined by qRT-PCR and ELISA.ResultsA significantly higher IL-37 protein level was observed in patients with AOSD than in HC. Serum IL-37 levels correlated with systemic score, laboratory values, IL-1β, IL-18, and IL-10 in patients with AOSD. The expression levels of IL-37 were closely related to the patients with AOSD who also had fever, skin rash, lymphadenopathy, splenomegaly, myalgia, and arthralgia. Moreover, the production of proinflammatory cytokines such as IL-6, IL-1β, TNF-α, and IL-18 in PBMCs from patients with AOSD was obviously attenuated after recombinant human IL-37 stimulation.ConclusionsIncreased expression of IL-37 and its positive correlation with disease activity suggest its involvement in AOSD pathogenesis. More importantly, IL-37 inhibits the expression of proinflammatory cytokines in PBMCs from patients with AOSD, indicating the potential anti-inflammatory role of IL-37 in AOSD. Thus, IL-37 may be a novel disease activity biomarker and research target in AOSD.

Highlights

Interleukin (IL)-37 has been known to play an immunosuppressive role in various inflammatory disorders, but whether it participates in the regulation of pathogenesis of adult-onset Still’s disease (AOSD) has not been investigated
Serum IL-37 levels were higher in patients with AOSD compared with healthy control subjects The serum IL-37 levels of 62 patients with AOSD and 50 age- and sex-matched HC were measured by enzyme-linked immunosorbent assay (ELISA)
Associations of serum IL-37 levels with inflammatory cytokines levels Published studies have demonstrated that proinflammatory cytokines IL-1β, tumor necrosis factor-α (TNF-α), IL-6, IL-18, and IL-17 play an important role in promoting AOSD disease development [14, 19, 40, 43, 44]. Consistent with these findings, we demonstrated that the levels of serum IL-1β, IL1Rα, TNF-α, soluble tumor necrosis factor receptor, IL6, IL-18, and IL-17 were significantly higher in patients a b c d e

Summary

Introduction

Interleukin (IL)-37 has been known to play an immunosuppressive role in various inflammatory disorders, but whether it participates in the regulation of pathogenesis of adult-onset Still’s disease (AOSD) has not been investigated. The pathogenic mechanism of AOSD is still largely unknown, multiple factors, including a predisposing genetic background, viral infections, and aberrant immune response, have been suggested to be involved in the development of this disease [4,5,6,7]. Proinflammatory cytokines, such as interleukin (IL)1β, IL-6, IL-18, tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ), have been found to be elevated during AOSD and are thought to be involved in the pathogenesis of AOSD [8,9,10,11,12,13]. Recent studies have indicated that IL-37 downregulated the expression of proinflammatory cytokines in chronic inflammatory diseases such as systemic lupus erythematosus (SLE) [24], rheumatoid arthritis (RA) [25,26,27], and ankylosing spondylitis (AS) [28], suggesting that IL-37 might abrogate proinflammatory cytokine production to reduce inflammatory responses in AOSD

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Conclusion