Elsevier

Cytokine

Volume 110, October 2018, Pages 291-297
Cytokine

Short communication
Elevated frequency of IL-37- and IL-18Rα-positive T cells in the peripheral blood of rheumatoid arthritis patients

https://doi.org/10.1016/j.cyto.2018.02.015Get rights and content

Highlights

  • IL-37 and IL-18Rα positive T cells were significantly elevated in RA patients.

  • IL-37 and its receptors may play an immunoregulatory role in the CD4+T activation.

  • IL-37 plays an important role in the regulation of inflammation in RA.

  • IL-37 may be a therapeutic target for rheumatoid arthritis.

Abstract

Objective

To detect the expression of IL-37 and its receptors IL-18Rα and IL-1R8 in CD4+ T cells and total lymphocytes in rheumatoid arthritis (RA) patients and the relationship between autoantibodies and disease activity. To investigate the mechanism of IL-37 and its receptors involved in the pathogenesis of RA. To evaluate the effects of different concentrations of rhIL-37 on peripheral blood mononuclear cells (PBMCs) in RA patients with TNF-α, and IL-6.

Methods

The expression of IL-37 and its receptor IL-18Rα and IL-1R8 in peripheral blood CD4+ T cells and total lymphocytes in RA patients and healthy controls were measured by flow cytometry. The levels of TNF-α and IL-6 in the supernatant were measured by ELISA after rhIL-37 stimulation with PBMCs.

Results

The expression of IL-37 and IL-18Rα in the total lymphocytes, especially in CD4+ T cells in RA patients, was significantly higher than in the healthy control group. There was a positive correlation between the frequency of IL-37- or IL-18Rα-positive CD4+ T cells and ESR, CRP, and DAS28 values. Additionally, rhIL-37 significantly down-regulated TNF-α and IL-6 production in RA patients’ PBMCs.

Conclusions

IL-37 plays an important role in the regulation of inflammation in RA. IL-37 and its receptors may play an immunoregulatory role in the activation of lymphocytes, especially CD4+ T cells, in RA patients. IL-37 may represent a therapeutic target for rheumatoid arthritis.

Introduction

Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial cell proliferation and lymphocyte invasion [1]. The abnormal activation of T lymphocytes, especially CD4-positive (CD4+) T cells, plays an important role in the development of RA [2]. Studies showed that interleukin (IL)-17 producing CD4+ T cells (Th17 cells) contribute to the pathogenesis of rheumatoid arthritis [3].

IL-37 is a newly identified cytokine that belongs to the IL-1 family. IL-37 is also called IL-1F7 [4]. IL-37 has a common constructor model with other members of the IL-1 family, especially IL-18 [5]. It has been demonstrated that IL-37 is a natural suppressor of the innate immune response [6], which has the effect of inhibiting local and systemic inflammatory responses [7]. IL-37 can significantly reduce the production of inflammatory cytokines in LPS-stimulated mouse primary macrophages [8]. Studies showed that IL-37 plays an important role in autoimmune diseases. Elevated serum and plasma levels of IL-37 were observed in RA, systemic lupus erythaematosus (SLE), and ankylosing spondylitis (AS) and were closely associated with disease activity [9]. IL-37 can inhibit the production of inflammatory cytokines by peripheral blood mononuclear cells (PBMCs) in autoimmune diseases [10], [11], [12], [13].

IL-37 binds to the receptor-IL-18Rα and recruits the orphan protein IL-1R8 instead of IL-18Rβ to form a three-type domain to silence the TLR joint molecule MyD88, weaken the MyD88 signal, inhibit transcription factors and exert an anti-inflammatory effect [14]. The anti-inflammatory effect of IL-37 is not observed in IL-18Rα knockout mice, and a lack of IL-1R8 primary mouse macrophages and dendritic cells is not associated with anti-inflammatory properties [14], [15], which provides the anti-inflammatory activity of a complex consisting of IL-37, IL-18Rα, and IL-1R8. However, how IL-37 exerts immunoregulatory effects in RA has not been thoroughly elucidated to date.

In this study, we measured the frequency of IL-37+ CD4+ T cells, IL-18Rα+ CD4+ T cells, and IL-1R8+ CD4+ T cells in RA patients and its association with clinical parameters. In addition, tumour necrosis factor (TNF)-α and IL-6 production levels by PBMCs after stimulation with recombinant human (rh) IL-37 were also investigated.

Section snippets

Patients

A total of 61 RA patients and 10 healthy controls (HCs) (age and sex matched) were recruited randomly from the Frist Affiliated Hospital of China Medical University. All RA patients fulfilled the American College of Rheumatism (ACR)/European League Against Rheumatism (EULAR) 2010 diagnostic criteria [16]. The laboratory assessments included evaluations of the erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF) and anti-cyclic citrullianted-peptide (anti-CCP)

Clinical characteristics of the RA patients

A total of 61 RA patients and 10 healthy volunteers were enrolled in this study. The clinical features are indicated in Table 1.

Increased frequency of IL-37+ CD4+ T cells and IL-37+ lymphocytes in PBMCs from RA patients

A total of 21 RA patients and 10 HCs were recruited for the study. We evaluated the frequency of IL-37 producing cells in CD4+, CD4 cells and total lymphocytes via flow cytometry. The frequency of IL-37+ CD4+ T cells was elevated in RA patients compared with the HCs (1.128 ± 0.3723% vs 0.6711 ± 0.3485%, p = 0.0029) (Fig. 1A). In contrast, no differences were observed

Discussion

In this study, we used flow cytometry to demonstrate that the expression of IL-37 in total lymphocytes, especially in CD4+ T cells in RA patients, was significantly higher than in healthy control subjects and positively correlated with CRP, ESR, and DAS28 that indicated disease activity. This finding suggests that the expression of IL-37 in activated CD4+ T cells could be involved in the immune response of RA. However, IL-37 was not associated with other clinical indicators of RF and CCP; this

Acknowledgments

Fund for China National Science Foundation (No. 81202347)

References (32)

  • A. Kosmaczewska et al.

    The role of Th1, Th17, and Treg cells in the pathogenesis of rheumatoid arthritis including anti-inflammatory action of Th1 cytokines

    Postepy. Hig. Med. Dosw. (Online)

    (2011)
  • M.F. Nold et al.

    IL-37 is a fundamental inhibitor of innate immunity

    Nature Immunol.

    (2010)
  • D. Boraschi et al.

    IL-37: a new anti-inflammatory cytokine of the IL-1 family

    Eur. Cytokine Network

    (2011)
  • S. Sharma et al.

    The IL-1 family member 7b translocates to the nucleus and down-regulates proinflammatory cytokines

    J. Immunol.

    (2008)
  • L. Ye et al.

    IL-37 alleviates rheumatoid arthritis by suppressing IL-17 and IL-17-triggering cytokine production and limiting Th17 cell proliferation

    J. Immunol.

    (2015)
  • L. Ye et al.

    IL-37 inhibits the production of inflammatory cytokines in peripheral blood mononuclear cells of patients with systemic lupus erythematosus: its correlation with disease activity

    J. Translational Med.

    (2014)
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