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