Immunoregulatory role of IL-35 in T cells of patients with rheumatoid arthritis

Nakano, Souichiro; Morimoto, Shinji; Suzuki, Satoshi; Tsushima, Hirofumi; Yamanaka, Kenjiro; Sekigawa, Iwao; Takasaki, Yoshinari

doi:10.1093/rheumatology/keu528

Cited by 61 publications

(45 citation statements)

References 22 publications

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“…42 While excess T H 1 cell and T H 17 cell activity can contribute to RA pathology, reduced frequencies of tolero genic regulatory T (T REG ) cells are also a feature of autoimmune disease that could similarly contribute to the pathology of RA. Consistent with this hypothesis, levels of anti-inflammatory cytokines such as IL-10, transforming growth factor β 43 and the novel IL-12-family cytokine IL-35 44,45 are reduced in serum from patients with RA. However, findings have been contradictory regarding the frequency of peripheral T REG cells in patients with RA relative to healthy controls, 46 and no difference in T REG cell frequency has been observed between patients with RA or osteoarthritis.…”

Section: Reviewsmentioning

confidence: 65%

Vitamin D in rheumatoid arthritis—towards clinical application

2015

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In addition to its well-documented involvement in mineral homeostasis, vitamin D seems to have broad effects on human health that go beyond the skeletal system. Prominent among these so-called nonclassical effects of vitamin D are its immunomodulatory properties. In vitro studies have shown anti-inflammatory effects of 1,25-dihydroxyvitamin D (1,25(OH)2D), the active form of vitamin D. In addition, epidemiological analysis of patients with established inflammatory disease identified associations between vitamin D deficiency (low serum concentrations of inactive 25-hydroxyvitamin D, abbreviated to 25(OH)D) and inflammatory conditions, including rheumatoid arthritis (RA). The association of vitamin D deficiency with RA severity supports the hypothesis of a role for vitamin D in the initiation or progression of the disease, or possibly both. However, whether 25(OH)D status is a cause or consequence of RA is still incompletely understood and requires further analysis in prospective vitamin D supplementation trials. The characterization of factors that promote the transition from preclinical to clinical phases of RA has become a major focus of research, with the aim to facilitate earlier diagnosis and treatment, and improve therapeutic outcomes. In this Review, we aim to describe the current knowledge of vitamin D and the immune system specifically in RA, and discuss the potential benefits that vitamin D might have on slowing RA progression.

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Section: Reviewsmentioning

confidence: 65%

Vitamin D in rheumatoid arthritis—towards clinical application

2015

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“…Human IL-35 expression has been reported in chronic hepatitis B virus-infected patients [31], normal pregnancies [32], sepsis [33], and rheumatoid arthritis [34]. In support of a mathematical modeling analysis that reported a correlation between IL-35 and tumors [16], we demonstrate that elevated IL-35 level in CRC patients is coincident with an increase in Treg cells and it was mainly expressed in CD4 + T cells in human colorectal cancer and adjacent tissues.…”

Section: Discussionmentioning

confidence: 99%

Elevated level of Interleukin-35 in colorectal cancer induces conversion of T cells into iTr35 by activating STAT1/STAT3

Chen

Xie

et al. 2016

Oncotarget

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IL-35 is a novel heterodimeric and inhibitory cytokine, composed of interleukin-12 subunit alpha (P35) and Epstein-Barr virus -induced gene 3 (EBI3). IL-35 has been reported to be produced by a range of cell types, especially regulatory T cells, and to exert immunosuppressive effects via the STATx signaling pathway. In this study, we demonstrated that IL-35 expression was elevated in both serum and tumors in patients with colorectal cancer. IL-35 mainly expressed in CD4+ T cells in human colorectal cancer tumors and adjacent tissues. Increased IL-35 expression in tumor-adjacent tissues was significantly associated with tumor metastasis. IL-35 inhibited the proliferation of CD4+CD25− T effector cells in vitro in a dose-dependent manner, and its suppression was partially reversed by applying IL-35-neutralizing antibodies. IL-35 treatment activated the phosphorylation of both STAT1 and STAT3 in human CD4+ T cells. Meanwhile, IL-35 induced a positive feedback loop to promote its own production. We observed that Tregs obtained from colorectal cancer patients were capable of inducing more IL-35 production. In addition, EBI3 promoter-driven luciferase activity was higher than that of the mock plasmid after IL-35stimulation. Thus, our study indicates that the high level of IL-35 in colorectal cancer promotes the production of IL-35 via STAT1 and STAT3, which suppresses T cell proliferation and may participate in tumor immunotolerance.

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“…A recently published study has indicated that IL-35-producing B cells play an important role in the regulation of immunity, and a potential therapeutic value for IL-35 production by B cells in autoimmune and infectious diseases has been proposed (Shen et al 2014). In another study, Nakano et al (2015) focused on the regulatory role of IL-35 in T cells of patients with RA. They observed that IL-35 exhibited an immunosuppressive role in T cell activation during the immune response elicited in RA.…”

Section: Discussionmentioning

confidence: 99%

Low Serum Levels of Interleukin 35 in Patients with Rheumatoid Arthritis

Xia

Jian

Wang

2015

Tohoku J. Exp. Med.

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Interleukin 35 (IL-35) is a newly discovered anti-inflammatory cytokine. Recent studies have indicated that it plays a crucial role in the pathogenesis of autoimmune diseases. In humans, IL-35 is predominantly secreted from regulatory T cells. This study aimed to measure serum IL-35 levels in patients with rheumatoid arthritis (RA) and in control individuals, and analyze its association with disease indicators of RA. One hundred patients with RA were recruited, and 50 volunteers were enrolled as healthy controls. Serum IL-35 levels were measured using an enzyme-linked immunosorbent assay kit. RA patients showed significantly lower serum levels of IL-35 compared with healthy controls (p < 0.001). RA patients suffering from erosive arthritis (n = 31) had lower IL-35 levels than those with non-erosive arthritis (n = 69, p = 0.022). In addition, serum IL-35 level was significantly lower in 22 patients with elevated percentage (> 75%) of neutrophils (p < 0.001). Correlation analysis indicated a significantly negative association between IL-35 and age, rheumatoid factor (RF), or percentage of neutrophils. In contrast, the serum IL-35 levels were not significantly different between patients with anti-cyclic citrullinated peptide (CCP) antibodies (n = 78) and those without anti-CCP antibodies (n = 22). However, among patients without anti-CCP antibodies, the serum IL-35 levels were lower in patients with erosive arthritis (n = 8) than those patients without erosion (n = 14) (p < 0.001), although no significant difference was detected in patients with anti-CCP antibodies. In conclusion, IL-35 plays a protective role in the pathogenesis of RA.

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Immunoregulatory role of IL-35 in T cells of patients with rheumatoid arthritis

Abstract: These data revealed that IL-35 might suppress T cell activation during the peripheral immune responses of RA. Therefore our data suggest that IL-35 might have multiple therapeutic targets.

Cited by 61 publications

References 22 publications

Vitamin D in rheumatoid arthritis—towards clinical application

Vitamin D in rheumatoid arthritis—towards clinical application

Elevated level of Interleukin-35 in colorectal cancer induces conversion of T cells into iTr35 by activating STAT1/STAT3

Low Serum Levels of Interleukin 35 in Patients with Rheumatoid Arthritis

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