IL-37 Alleviates Rheumatoid Arthritis by Suppressing IL-17 and IL-17-Triggering Cytokine Production and Limiting Th17 Cell Proliferation.

IL-37, a new member of the IL-1 cytokine family, is a natural inhibitor of innate immunity associated with autoimmune diseases. This study was undertaken to evaluate whether IL-37 has antiarthritic effects in patients with rheumatoid arthritis (RA) and in mice with collagen-induced arthritis (CIA). In this study, we analyzed the expression of IL-37 in PBMCs, serum, and lymphocytes from RA patients as well as CD4(+) T cells polarized under Th1/Th2/Th17 conditions. The role of IL-37 was assessed by investigating the effects of recombinant human (rh)IL-37 and an adenovirus encoding human IL-37 (Ad-IL-37) on Th17 cells and Th17-related cytokines in RA patients and CIA mice. We found that active RA patients showed higher IL-37 levels compared with patients with inactive RA and healthy controls. Upregulated IL-37 expression also was found in CD3(+) T cells and CD4(+) T cells from RA patients and in Th1/Th17-differentiation conditions. rhIL-37 markedly decreased IL-17 expression and Th17 cell frequency in PBMCs and CD4(+) T cells from RA patients. Furthermore, IL-37 exerted a more suppressive effect on Th17 cell proliferation, whereas it had little or no effect on Th17 cell differentiation. IL-17 and IL-17-driving cytokine production were significantly reduced in synovium and joint cells from CIA mice receiving injections of Ad-IL-37. Our findings indicate that IL-37 plays a potent immunosuppressive role in the pathogenesis of human RA and CIA models via the downregulation of IL-17 and IL-17-triggering cytokine production and the curbing of Th17 cell proliferation.

Interleukin-37 is increased in ankylosing spondylitis patients and associated with disease activity.

BACKGROUND: Interleukin-37 (IL-37) has been known to play an immunosuppressive role in various inflammatory disorders, but whether it participates in the regulation of pathogenesis of ankylosing spondylitis (AS) has not been investigated. Here, we examined the serum levels of IL-37 and its clinical association in AS, and explored the anti-inflammatory effects of IL-37 on peripheral blood mononuclear cells (PBMCs) from AS patients. METHODS: The mRNA levels of IL-37, TNF-α, IL-6, IL-17, and IL-23 in PBMCs and their serum concentrations from 46 AS patients were examined by real-time polymerase chain reaction (RT-PCR) and enzyme-linked immunoassay (ELISA), respectively. The correlations between serum IL-37 levels with disease activity, laboratory values and pro-inflammatory cytokines in AS were analyzed by Spearman correlation test. PBMCs from 46 AS patients were stimulated with recombinant IL-37 protein, expressions of TNF-α, IL-6, IL-17 and IL-23 were determined by RT-PCR and ELISA. RESULTS: Compared to healthy controls (HC), AS patients and active AS patients showed higher levels of IL-37 in PBMCs and serum respectively. Strikingly, serum IL-37 levels were higher in AS patients with osteoporosis than those without. Serum levels of IL-37 were correlated with laboratory values as well as TNF-α, IL-6 and IL-17, but not IL-23 in patients with AS. The productions of pro-inflammatory cytokines such as TNF-α, IL-6, IL-17, IL-23 in PBMCs from AS patients were obviously attenuated after recombinant IL-37 stimulation, but not in the HC. CONCLUSION: The higher levels of IL-37 were found in AS patients, which were correlated with disease activity and AS related pro-inflammatory cytokines. More importantly, IL-37 inhibits the expressions of the pro-inflammatory cytokines from PBMCs in AS patients, indicating the potential anti-inflammatory role of IL-37 in AS.

Increased expression of IL-37 in patients with Graves' disease and its contribution to suppression of proinflammatory cytokines production in peripheral blood mononuclear cells.

BACKGROUND: Interleukin-37 (IL-37), a member of IL-1 family, is primarily an anti-inflammatory cytokine, which reduces systemic and local inflammation. However, the expression and role of IL-37 in Graves' disease (GD) remains unknown. This study aims to measure the levels of serum and peripheral blood mononuclear cells (PBMCs) IL-37 in patients with Graves' disease and to examine its association with disease activity. Furthermore, we investigate the effect of IL-37 on proinflammatory cytokines involved in the pathogenesis of GD. METHODS: The expressions of IL-37, TNF-α, IL-6, and IL-17 mRNA in peripheral blood mononuclear cells (PBMCs) of 40 patients with Graves' disease were determined by real-time reverse transcription-polymerase chain reaction (RT-PCR), and the levels of IL-37, TNF-α, IL-6, and IL-17 in serum were detected by enzyme-linked immunoassay (ELISA). The correlation of serum IL-37 levels with cytokines and disease activity in Graves' disease patients were investigated. The expressions of cytokines TNF-α, IL-6, and IL-17 in PBMCs under recombinant IL-37 stimulation were determined by RT-PCR and ELISA respectively. RESULTS: The levels of IL-37, TNF-α, IL-6, and IL-17 in PBMCs and serum were significantly increased in patients with GD compared with healthy controls (HC). Serum IL-37 were closely correlated with TNF-α, IL-6, IL-17, thyrotropin (TSH), free thyroxine (FT4),free triiodothyronine (FT3) and thyrotropin receptor antibody (TRAB). GD patients with active disease showed higher IL-37 mRNA and serum protein levels compared with those with inactive disease as well as HC. Moreover, IL-37 suppressed the production of IL-6, IL-17 and TNF-α in PBMCs of patients with GD. CONCLUSIONS: Increased level of IL-37 in patients with GD are associated with TNF-α, IL-6, IL-17 and disease activity, and it plays a protective role against inflammatory effect in GD by inhibiting the production of proinflammatory cytokines. Thus, IL-37 may provide a novel research target for the pathogenesis and therapy of GD.