Autoimmune diseases (ADs) are characterized by the production of autoreactive lymphocytes, immune responses to self-antigens, and inflammation in related tissues and organs. Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is majorly expressed in activated T cells and works as a critical regulator in the inflammatory response. In this review, we first describe the structure, expression, and how the signaling pathways of CTLA-4 participate in reducing effector T-cell activity and enhancing the immunomodulatory ability of regulatory T (Treg) cells to reduce immune response, maintain immune homeostasis, and maintain autoimmune silence. We then focused on the correlation between CTLA-4 and different ADs and how this molecule regulates the immune activity of the diseases and inhibits the onset, progression, and pathology of various ADs. Finally, we summarized the current progress of CTLA-4 as a therapeutic target for various ADs.

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 (IL-37), a new member of IL-1 family cytokine, is recently identified as a natural inhibitor of innate immunity. This study aimed to measure the peripheral blood mononuclear cells (PBMCs) and serum levels of IL-37 in patients with systemic lupus erythematosus (SLE) and to investigate its role in SLE, including its correlation with disease activity, organ disorder and the regulation of inflammatory cytokines. The expressions of IL-37 mRNAs in PBMCs and serum IL-37 levels in 66 SLE patients were measured by real-time polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). SLE patients PBMCs were stimulated with recombinant IL-37, levels of cytokines TNF-α, IL-1β, IL-6 and IL-10 were detected by RT-PCR and ELISA. IL-37 mRNAs and serum protein levels were higher in patients with SLE compared with healthy controls. Patients with active disease showed higher IL-37 mRNAs and serum protein levels compared with those with inactive disease as well as healthy controls. Serum IL-37 levels correlated with SLEDAI and inversely with C3 and C4. Serum IL-37 levels were higher in SLE patients with renal involvement compared with those without renal disease. In vitro, IL-37 inhibited the production of TNF-α, IL-1β and IL-6 in PBMCs of patients with SLE, whereas the production of IL-10 was unaffected. IL-37 associated with SLE disease activity, especially related with SLE renal disease activity. IL-37 is an important cytokine in the control of SLE pathogenesis by suppressing the production of inflammatory cytokines. Thus, IL-37 may provide a novel research target for the pathogenesis and therapy of SLE.

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. 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. 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. 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.

Significance Statement: Although mesenchymal stem cells might have potential for treating SLE, their immunoregulatory plasticity renders their therapeutic effects unpredictable. The authors genetically modified mesenchymal stem cells to overexpress IL-37—a protein with immunosuppressive activity—and assessed the modified cells’ effects on immune suppression in vitro, as well as the effects of transplanting such cells into a mouse model of SLE. Mice transplanted with IL-37–overexpressing cells displayed improved survival and reduced signs of SLE compared with controls. Expression of IL-37 by mesenchymal stem cells can maintain higher serum levels of IL-37, and these cells had prolonged survival after transplantation, perhaps through IL-37 suppressing the inflammatory microenvironment. The additive therapeutic effects of this approach might offer a way to enhance the stability and effectiveness of mesenchymal stem cells in treating SLE. Background: Although mesenchymal stem cells (MSCs) might offer a promising strategy for treating SLE, their immunoregulatory plasticity makes their therapeutic effects unpredictable. Whether overexpressing IL-37, an IL-1 family member with immunosuppressive activity, might enhance the therapeutic effects of these cells for SLE is unknown. Methods: We genetically modified MSCs to overexpress IL-37 and assessed their effects on immune suppression in vitro. We also evaluated the effects of such cells versus effects of various controls after transplanting them into MRL/lpr mice (model of SLE). Results: Stem cell characteristics did not appear altered in MSCs overexpressing IL-37. These cells had enhanced immunosuppression in vitro in terms of inhibiting splenocyte proliferation, reducing proinflammatory factors (IL-1β, TNF-α, IL-17, and IL-6), and suppressing autoantibodies (anti-dsDNA and anti-ANA). Compared with animals receiving control MSCs or IL-37 treatment alone, MRL/lpr mice transplanted with IL-37–overexpressing cells displayed improved survival and reduced signs of SLE (indicated by urine protein levels, spleen weight, and renal pathologic scores); they also had significantly lower expression of proinflammatory factors, lower total antibody levels in serum and urine, lower autoantibody production, and showed reduced T cell numbers in the serum and kidney. Expression of IL-37 by MSCs can maintain higher serum levels of IL-37, and MSCs had prolonged survival after transplantation, perhaps through IL-37 suppressing the inflammatory microenvironment. Conclusions: Mutually reinforcing interaction between MSCs and IL-37 appears to underlie their additive therapeutic effects. Genetic modification to overexpress IL-37 might offer a way to enhance the stability and effectiveness of MSCs in treating SLE.

Introduction: Our objective in the present study was to determine the signaling pathway of interleukin 10 (IL-10) for modulating IL-17 expression in macrophages and the importance of this mediation in collagen-induced arthritis (CIA). Methods: IL-10-knockout (IL-10^−/−) mice and wild-type (WT) mice were immunized with chicken type II collagen (CII) to induce arthritis. The expression levels of IL-17 and retinoid-related orphan receptor γt (RORγt) in macrophages and joint tissues of IL-10^−/− and WT mice were analyzed by enzyme-linked immunosorbent assay, quantitative RT-PCR (qRT-PCR) and Western blotting. The F4/80 macrophages and positive IL-17-producing macrophages in synovial tissues of the mice were determined by immunohistochemistry. The populations of classically activated macrophage (M1) and alternatively activated macrophage (M2) phenotypes were analyzed by flow cytometry. The expression of genes associated with M1 and M2 markers was analyzed by qRT-PCR. Results: Compared to WT mice, IL-10^−/− mice had exacerbated CIA development, which was associated with increased production of T helper 17 cell (Th17)/Th1 proinflammatory cytokines and CII-specific immunoglobulin G2a antibody after CII immunization. Macrophages in IL-10^−/− mice had increased amounts of IL-17 and RORγt compared with the amounts in WT mice with CIA. Immunofluorescence microscopy showed that the number of IL-17-producing macrophages in synovial tissues was significantly higher in IL-10^−/− mice than in WT mice. IL-10 deficiency might promote macrophage polarization toward the proinflammatory M1 phenotype, which contributes to the rheumatoid arthritis inflammation response. Conclusion: IL-10 inhibits IL-17 and RORγt expression in macrophages and suppresses macrophages toward the proinflammatory M1 phenotype, which is important for the role of IL-10 in mediating the pathogenesis of CIA.