Low Serum Levels of Interleukin 35 in Patients with Rheumatoid Arthritis

Xia, Ning; Jian, Zijuan; Wang, Wei

doi:10.1620/tjem.237.77

Cited by 33 publications

(27 citation statements)

References 32 publications

(31 reference statements)

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“…Based on its immunological functions, IL-35 has been studied in the context of many autoimmune diseases. For instance, patients with RA (Ning et al 2015) or idiopathic thrombocytopenic purpura (Yang et al 2014b) showed below-normal serum concentrations of IL-35. In RA, IL-35 was negatively related to the concentration of rheumatoid factor and percentage of neutrophils (Ning et al 2015).…”

Section: Discussionmentioning

confidence: 99%

“…For instance, patients with RA (Ning et al 2015) or idiopathic thrombocytopenic purpura (Yang et al 2014b) showed below-normal serum concentrations of IL-35. In RA, IL-35 was negatively related to the concentration of rheumatoid factor and percentage of neutrophils (Ning et al 2015). In idiopathic thrombocytopenia purpura, IL-35 concentration was positively correlated with the numbers of circulating platelets and Tregs, but negatively correlated with the number of Th1 cells (Yang et al 2014b).…”

Section: Discussionmentioning

confidence: 99%

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Lower Plasma Levels of IL-35 in Patients with Primary Biliary Cirrhosis

Huang

Liu

et al. 2018

Tohoku J. Exp. Med.

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Primary biliary cirrhosis (PBC) is an autoimmune liver disease. Its histological characteristics, such as progressive intrahepatic bile duct destruction, cholestasis, and liver cirrhosis, are caused by the body's autoimmune disorders. Interleukin (IL)-35 has two subunits (p35 and Ebi3) and is a member of the IL-12 family of heterodimeric cytokines. IL-35 has immunosuppressive functions and plays an important role in many autoimmune diseases. In this study, we compared plasma levels of IL-35 and relative mRNA expression levels of p35 and Ebi3 in peripheral blood mononuclear cells (PBMCs) from 70 PBC patients and 70 healthy individuals. The results showed that the relative expression levels of Ebi3 mRNA were lower in PBMCs from PBC patients than in PBMCs from healthy individuals, whereas the levels of p35 mRNA were similar in both groups. Plasma IL-35 concentrations were lower in patients with PBC than in healthy individuals. Plasma levels were higher in PBC patients at an advanced stage compared to patients at an early stage. Variable plasma levels with different stages were also found in transforming growth factor beta (TGF-β), which is mainly produced by regulatory T cells (Tregs). IL-35 and TGF-β levels were positively correlated with each other, and IL-35 was capable of promoting the inhibitory functions of Tregs in PBC patients at both the early and late stages of disease. Lower plasma IL-35 levels were accompanied by higher levels of typical clinical parameters, such as alkaline phosphatase, or of proinflammatory cytokines, such as interferon-gamma (IFN-γ), in PBC patients (P < 0.05 for each). We propose that IL-35 may be involved in the pathogenesis of PBC and could be a potential biomarker for diagnosing this disease.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Lower Plasma Levels of IL-35 in Patients with Primary Biliary Cirrhosis

Huang

Liu

et al. 2018

Tohoku J. Exp. Med.

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“…Several studies have assessed the role of IL-35 in autoimmune diseases; in a mouse model, Niedbala et al (16) revealed that recombinant IL-35 effectively attenuated collagen-induced arthritis, and a subsequent study by Kochetkova et al (17) reported similar results. Several clinical studies indicated that serum IL-35 levels were significantly lower in patients with RA; furthermore, treatment with IL-35 suppressed inflammatory cytokine levels and enhanced the regulatory function of Tregs (18,19). However, few studies have analyzed the number and function of Tregs in patients with RA.…”

Section: Introductionmentioning

confidence: 99%

Decreased regulatory T‑cell frequency and interleukin‑35 levels in patients with rheumatoid arthritis

Zhang

Zhuang

et al. 2018

Exp Ther Med

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Interleukin-35 (IL-35) is a newly discovered anti-inflammatory cytokine predominantly released by regulatory T cells (Tregs) and may serve an important role in the pathogenesis of autoimmune diseases. The levels of IL-35 and corresponding Treg frequencies in patients with rheumatoid arthritis (RA) have scarcely been reported. The present study aimed to detect serum IL-35 levels and Treg frequencies in patients with RA, and analyze their association with each other and with indicators of RA. A total of 55 patients with RA, including 37 active-phase (AP) and 18 chronic-phase (CP) cases, as well as 20 healthy controls (HC), were recruited. Clinical parameters, including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) levels, rheumatoid factor (RF), anti-cyclic citrullinated peptide (CCP) antibody and 28-joint disease activity score (DAS28) were assessed. The Treg frequency in peripheral blood (PB) was determined by flow cytometry. IL-35 mRNA in PB mononuclear cells of the patients with RA was measured by reverse transcription-quantitative polymerase chain reaction analysis, and IL-35 levels in the serum were detected by ELISA. The correlations between IL-35 levels and the abovementioned indexes were analyzed by determining Pearson's correlation coefficient. The results of the present study indicated that the Treg frequency was significantly decreased in patients with RA compared with that in HC. No significant difference in Treg frequency between the AP and CP groups of RA patients was identified. In addition, the serum IL-35 levels and mRNA expression in RA patients were obviously lower than those in the HC. Of note, the serum IL-35 levels were negatively correlated with the ESR and DAS28 of patients with RA, while no correlation with CRP, RF or anti-CCP antibodies was identified. In addition, a significant positive correlation was revealed between serum IL-35 levels and the Treg frequency. These results suggest that IL-35 and Tregs have a protective role regarding the development of RA.

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“…IL‐35 is a recently discovered member of the IL‐12 cytokine family consisting of Epstein‐Barr‐virus‐induced gene 3 (Ebi3) and IL‐12α subunits . Unlike other members of this cytokine family, IL‐35 exhibits only immunosuppressive properties and has been shown to mediate protection in several diseases in both humans and mouse models . IL‐35 is secreted by and contributes to the suppressor function of Foxp3 + Treg .…”

Section: Introductionmentioning

confidence: 99%

β‐cell‐specific IL‐35 therapy suppresses ongoing autoimmune diabetes in NOD mice

Manzoor

Johnson

et al. 2016

Eur J Immunol

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IL-35 is a recently identified cytokine exhibiting potent immunosuppressive properties. The therapeutic potential and effects of IL-35 on pathogenic T effector (Teff) cells and Foxp3+ Treg cells, however, are ill-defined. We tested the capacity of IL-35 to suppress ongoing autoimmunity in NOD mice. For this purpose, an adeno-associated virus vector in which IL-35 transgene expression is selectively targeted to β cells via an insulin promoter (AAV8mIP-IL35) was used. AAV8mIP-IL35 vaccination of NOD mice at a late preclinical stage of type 1 diabetes (T1D) suppressed β-cell autoimmunity and prevented diabetes onset. Numbers of islet-resident conventional CD4+ and CD8+ T cells, and DCs were reduced within 4 weeks of AAV8mIP-IL35 treatment. The diminished islet T-cell pool correlated with suppressed proliferation, and a decreased frequency of IFN-γ-expressing Teff cells. Ectopic IL-35 also reduced islet Foxp3+ Treg-cell numbers and proliferation, and protection was independent of induction/expansion of adaptive islet immunoregulatory T cells. These findings demonstrate that IL-35-mediated suppression is sufficiently robust to block established β-cell autoimmunity, and support the use of IL-35 to treat T1D and other T-cell-mediated autoimmune diseases.

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Low Serum Levels of Interleukin 35 in Patients with Rheumatoid Arthritis

Cited by 33 publications

References 32 publications

Lower Plasma Levels of IL-35 in Patients with Primary Biliary Cirrhosis

Lower Plasma Levels of IL-35 in Patients with Primary Biliary Cirrhosis

Decreased regulatory T‑cell frequency and interleukin‑35 levels in patients with rheumatoid arthritis

β‐cell‐specific IL‐35 therapy suppresses ongoing autoimmune diabetes in NOD mice

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