Interleukin-37 is increased in adult-onset Still’s disease and associated with disease activity

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.Electronic supplementary materialThe online version of this article (10.1186/s13075-018-1555-6) contains supplementary material, which is available to authorized users.

Plasma interleukin-37 is increased and inhibits the production of inflammatory cytokines in peripheral blood mononuclear cells in systemic juvenile idiopathic arthritis patients

“…IL-37 has been found as a natural inhibitor of inflammation and plays an important regulatory role in immune response by suppressing excessive inflammation [ 18 , 26 ]. Studies have confirmed that IL-37 can attenuate inflammation in chronic inflammatory diseases, such as SLE, RA, AS and ASOD [ 12 , 13 , 16 , 29 ]. Based on the above findings, we are eager to know whether and how IL-37 regulates inflammation induced by inflammatory cytokines in sJIA.…”

“…In vivo experiments found that silencing endogenous IL-37 with small interfering RNAs in PBMCs dramatically upregulated the secretions of IL-1β, IL-6, and TNF-α after LPS treatment [ 18 ]. Additionally, in vitro experiments revealed that recombinant IL-37 proteins effectively inhibit the production of IL-1β, IL-6, and TNF-α in PBMCs from SLE, AS and AOSD patients [ 12 , 13 , 16 ]. An interesting question that emerges from these findings is “What is the function of IL-37 expression in the process of sJIA inflammatory response?” To answer this question, the rhIL-37 protein was used to stimulate PBMCs from patients with sJIA and healthy controls.…”

“…However, the studies related to the expression and function of anti-inflammatory cytokines in sJIA remain poorly understood. IL-37, formerly named IL-1F7, downregulated the expression of pro-inflammatory cytokines in various inflammatory diseases [ 11 ], such as ankylosing spondylitis (AS), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and adult-onset Still’s disease (AOSD) [ 12 – 16 ], then relieving the inflammatory responses in sJIA.…”

“…When it is stimulated by lipopolysaccharide (LPS) or pro-inflammatory cytokines, the expression level of IL-37 is significantly upregulated and stability of IL-37 mRNA is markedly enhanced, suggesting IL-37 might play a primary role in suppressing excessive immune response [ 17 ]. In recent years, accumulating studies have found that IL-37 is closely related to inflammatory and autoimmune diseases, including SLE, RA, and AOSD [ 13 – 16 , 20 – 22 ]. Concomitantly, IL-37 can inhibit the production of pro-inflammatory cytokines in PBMCs from subjects with SLE, RA, AS and AOSD in vitro.…”

Urinary Proteomics Identifying Novel Biomarkers for the Diagnosis of Adult-Onset Still’s Disease

“…Most importantly, macrophage and neutrophil activation–associated inflammatory cytokine storms play a crucial role in the disease progression of AOSD ( 1 – 3 ). Pathogen-associated molecular patterns or danger-associated molecular patterns trigger inflammasome activation and the production of interleukin 1β (IL-1β) and IL-18, further improving the expression of the proinflammatory cytokines tumor necrosis factor α (TNF-α) and IL-6 and the anti-inflammatory cytokines IL-10 and IL-37 ( 1 , 6 , 7 ). Additionally, a markedly high frequency of elevated serum molecules such as alarmins (S100A8/A9 and S100A12), chemokines (C-X-C motif chemokine ligand 9, 10, and 11), and microRNAs, which correlate with disease activity, was noticed in patients with AOSD ( 8 – 12 ).…”