The immunoregulatory role of IL-35 in patients with interstitial lung disease

Pulmonary fibrosis involves various types of immune cells and soluble mediators, including TGF-β and IL-35, a recently identified heterodimeric cytokine that belongs to the IL-12 cytokine family. However, the effect of regulatory IL-35 may play an important role in fibrotic diseases. The aim of this paper is to explore the immunoregulatory role of IL-35 in the development of fibrosis in interstitial lung disease (ILD). To gain a better understanding of this issue, the concentrations of IL-35 and different profibrotic cytokines in fibrotic (F-ILD) and non-fibrotic (NF-ILD) patients by ELISA were compared to that of intracellular IL-35 and IL-17 on CD4+ T cells stimulated in the presence of BAL or with different ratios of recombinant IL-35 (rIL-35) and TGF-β (rTGF-β), which were evaluated by flow cytometry. We observed that BAL concentration of IL-35 was lower in F patients (p < 0.001) and was negatively correlated with concentrations of TGF-β (p < 0.001) and IL-17 (p < 0.001). In supplemented cell cultures, BAL from NF but not F patients enhanced the percentage of IL-35 + CD4+ T (p < 0.001) cells and decreased the percentage of IL-17 + CD4+ T cells (p < 0.001). The percentage of IL-35 + CD4+ T cells correlated positively with BAL concentration of IL-35 (p = 0.02), but correlated negatively with BAL concentrations of IL-17 (p = 0.007) and TGF-β (p = 0.01). After adjusting the concentrations of recombinant cytokines to establish a TGF-β: IL-35 ratio of 1:4, an enhanced percentage of IL-35 + CD4+ T cells (p < 0.001) but a decreased percentage of IL-17 + CD4+ T cells (p < 0.001) was observed. After adding recombinant IL-35 to the BAL from F patients until a 1:4 ratio of TGF-β: IL-35 was reached, a significantly increased percentage of IL-35 + CD4+ T cells (p < 0.001) and a decreased percentage of IL-17 + CD4+ T cells (p = 0.003) was found. These results suggest that IL-35 may induce an anti-fibrotic response, regulating the effect of TGF-β and the inflammatory response on CD4+ T cells. In addition, the TGF-β: IL-35 ratio in BAL has been shown to be a potential biomarker to predict the outcome of F patients with ILD.     

IL-35通过诱导T细胞分化促进肺癌肿瘤进展

目的 探究肺癌中IL-35对T细胞表型及对癌症进展的影响.方法 建立小鼠肺癌移植瘤模型,施用IL-35中和抗体,监测肿瘤生长情况.并通过检测肿瘤中T细胞的浸润情况及其表型和细胞因子分泌情况,进一步探究对抗肿瘤免疫反应的影响.最后通过对肿瘤浸润T细胞的体外刺激实验,检测浸润T细胞的抗肿瘤活性.结果 瘤体积及瘤重的检测结果...     

Assessing the role of IL-35 in colorectal cancer progression and prognosis

Despite the recent realization of Interleukin (IL)-35 in tumorigenesis, its exact impact on colorectal cancer (CRC) progression and prognosis, however, is yet to be elucidated clearly. We thus in the present report conducted comparative analysis of IL-35 levels between CRC patients and matched control subjects. IL-35 is highly expressed in all CRC tissues, which can be detected in vast majority of colorectal cancer cells. IL-35 levels in CRC lysates and serum samples are highly correlated to the severity of malignancy and the clinical stage of tumor. Particularly, a significant reduction for serum IL-35 was noted in patients after surgical resection, indicating that IL-35 promotes CRC progression associated with poor prognosis. Mechanistic study demonstrated a significant correlation between serum IL-35 levels and the number of peripheral regulatory T (Treg) cells in CRC patients, suggesting that IL-35 implicates in CRC pathogenesis probably by inducing Treg cells, while cancer cell-derived IL-35 may also recruit Treg cells into the tumor microenvironment in favor of tumor growth. Together, our data support that IL-35 could be a valuable biomarker for assessing CRC progression and prognosis in clinical settings.     

IL-35 promoted STAT3 phosphorylation and IL-10 production in B cells,but its production was reduced in patients with coronary artery diseases

Interleukin (IL)-35 is a heterodimeric cytokine composed of the IL-12A subunit and the Epstein-Barr virus induced gene 3 (EBI3) subunit. Binding of IL-35 with IL-12 receptor subunit beta 2 (IL-12RB2) and IL-6 signal transducer (IL-6ST) occupies the binding sites of IL-6, IL-12, and IL-27 and prevents their signal transduction. IL-35 is also shown to promote the development of regulatory T cells (Tregs) and regulatory B cells (Bregs). In this study, we investigated B cell-mediated IL-35 production in patients with coronary artery disease (CAD). The expression levels of IL-35 subunits and IL-10 were significantly lower in B cells from CAD patients than in B cells from healthy control individuals. Exogenous IL-35 could effectively increase the IL-10 production by B cells in a concentration-dependent manner. IL-35 promoted the phosphorylation of STAT1 and STAT3 in B cells, and the inhibition of STAT3 phosphorylation suppressed IL-10 production. Raising the IL-35 concentration in cell culture eliminated the difference in IL-10 expression between CAD B cells and healthy B cells. We also demonstrated that B cells from CAD patients presented lower capacity to suppress interferon gamma (IFNG) and tumor necrosis factor (TNF) expression by T cells than B cells from healthy controls. Exogenous IL-35 could significantly improve the suppressive capacity of B cells in both healthy controls and CAD patients. Together, these results demonstrated that a reduction in IL-35 production was associated with Breg defects in CAD patients. IL-35 and IL-35 targets may serve as therapeutic candidates in the treatment of CAD and related diseases.     

Emerging role of galectin family in inflammatory autoimmune diseases

Galectin family is a group of glycan-binding proteins. Members in this family are expressed in different tissues, immune or non-immune cells. These molecules are important regulators in innate and adaptive immune response, performing significantly in a broad range of cellular and pathophysiological functions, such as cell proliferation, adhesion, migration, and invasion. Findings have shown that expression of galectins is abnormal in many inflammatory autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, osteoarthritis, sjögren's syndrome, systemic sclerosis. Galectins also function as intracellular and extracellular disease regulators mainly through the binding of their carbohydrate recognition domain to glycoconjugates. Here, we review the state-of-the-art of the role that different galectin family members play in immune cells, contributing to the complex inflammatory diseases. Hopefully collection of the information will provide a preliminary theoretical basis for the exploration of new targets for treatment of the disorders.     

The immunomodulatory role of interleukin-35 in fibrotic diseases

Introduction: Fibrosis makes numerous diseases in all organs more complicated and leads to severe consequences in the lung, liver, heart, kidney, and skin. In essence, fibrosis results from excessive, persistent and oftentimes nonreversible aggregation of extracellular matrix (ECM) or simply as collagen during the process of tissue injury and repair. Recent studies suggest the pathology of fibrosis, especially in pulmonary and liver fibrosis, involves various types of immune cells and soluble mediators including interleukin (IL)-35, a recently identified heterodimeric cytokine that belongs to the IL-12 cytokine family. Furthermore, IL-35 may inhibit fibrotic diseases. However, the side effects of inhibiting IL-35 also need attention and we have a long way to go to make better use of it in fibrotic diseases.

Areas covered: This review focuses on recent evidence regarding the role of IL-35 in the pathogenesis of pulmonary, hepatic, cardiac, renal and skin fibrosis. It also discusses targeting of IL-35 as a promising novel strategy for treatment of fibrotic diseases.

Expert commentary: Understanding as fully as possible the relationship between IL-35 and fibrotic diseases is important for the development of new therapeutic approaches.     

新型免疫抑制因子IL-35研究新进展

IL-35是一种由调节性T细胞(Tr)分泌具有免疫负调作用的新型细胞因子.IL-35通过抑制IL-17等效应分子发挥免疫调节作用,研究表明,Tr、IL-35和Th17参与了自身免疫性疾病,炎症与肿瘤的免疫调节,因此IL-35的上游激活以及下游效应反应机制值得进一步研究探讨.     

Elevated IL-35 in bone marrow of the patients with acute myeloid leukemia

Acute myeloid leukemia (AML) is the most common hematological malignancy in adults, but the etiology of it remains poorly understood. IL-35 is a recently described cytokine composed of an IL-12 subunit p35 and an IL-27 subunit Epstein–Barr virus induced gene 3 (EBI3), and has an immunosuppressive effect on inflammation through induction of regulatory T cells (Tregs) and suppression of Th1 and Th17. Recently, we have illustrated that concentrations of IL-35 in peripheral blood are up-regulated in newly diagnosed (ND) AML patients. However, whether IL-35 in bone marrow is increased in AML patients is not clear. In this study, we examined IL-35 in bone marrow by various methods including RT-PCR, ELISA, FCM and IHC, and found that IL-35 levels are also increased significantly in bone marrow of adult AML patients. Furthermore, we investigated that concentrations of bone marrow IL-35 in ND group were higher than that in complete remission (CR) group and control group, but there was no significant difference compared to that in relapse group. In conclusion, IL-35 was elevated in bone marrow of adult AML patients and this increase was correlated with the clinical stages of malignancy, suggesting that IL-35 is involved in pathogenesis of AML.     

IL-35研究进展

细胞因子在介导机体针对病原微生物的免疫反应、自身免疫耐受以及维持机体内环境平衡等过程中起了重要作用,IL-35是最近几年新发现的细胞因子,属于IL-12细胞因子家族,对免疫系统和免疫反应有负向抑制作用。本文对这一新细胞因子生物学特性的研究现状作一综述。     

IL-21及其在自身免疫病中的研究进展

白介素-21(IL-21)是近年来被发现和关注的一个四螺旋束的细胞因子,主要由活化的CD4~+Th细胞和NKT细胞分泌,与IL-2、IL-4和IL-15具有高度同源性。它的受体属于Ⅰ型细胞因子受体,由α链和γc链组成,广泛分布于T细胞、B细胞、自然杀伤细胞、树突状细胞、巨噬细胞和角质化细胞等细胞表面,在固有免疫和适应性免疫中发挥重要作用。IL-21具有多效性,在类风湿性关节炎、系统性红斑狼疮、炎症性肠病等一些自身免疫病的发病机制中起着重要的作用。本文就IL-21及其与自身免疫病的关系作一综述。     

Interleukin-21 in autoimmune and inflammatory skin diseases

Studies on the role of interleukins (ILs) in autoimmune and inflammatory diseases allow for the better understanding of pathologic mechanisms of disease and reshaping of treatment modalities. The development of monoclonal antibodies targeting specific ILs or IL signaling pathways (i.e., anti-IL-17/IL-23 in psoriasis or anti-IL-4/IL-13 in atopic dermatitis) is the shining example of therapeutic interventions in research. IL-21, belonging to the group of ɣc-cytokines (IL-2, IL-4, IL-7, IL-9, and IL-15), is gaining attention for its pleiotropic role in several types of immune cells as activator of various inflammatory pathways. In both health and disease, IL-21 sustains T- and B-cell activity. Together with IL-6, IL-21 helps to generate Th17 cells, promotes CXCR5 expression in T cells, and their maturation into follicular T helper cells. In B cells, IL-21 sustains their proliferation and maturation into plasma cells and promotes class switching and antigen-specific antibody production. Due to these characteristics, IL-21 is a main factor in numerous immunologic disorders, such as rheumatoid arthritis and MS. Studies in preclinical skin disease models and on human skin strongly suggest that IL-21 is crucially involved in inflammatory and autoimmune cutaneous disorders. Here, we summarize the current knowledge of IL-21 in well-known skin diseases.     

IL-21在自身免疫性疾病中的作用

白细胞介素21(IL-21)是IL-2家族中的新成员,主要由活化的CD4+T细胞产生.IL-21具有广泛的生物学功能,主要调节T细胞、B细胞、NK细胞的功能.近年来IL-21与自身免疫性疾病的关系得到了广泛的研究,为自身免疫性疾病的治疗提供了新的思路和方法.     

Decreased IL-35 levels in patients with immune thrombocytopenia

IL-35 is a novel heterodimeric anti-inflammatory cytokine consisting of Epstein–Barr virus-induced gene 3 (EBI3) and the p35 subunit of IL-12. IL-35 has been shown to possess the potency of inhibiting the CD4+ effector T cells and alleviating autoimmune diseases. In the study we investigated the levels of IL-35 as well as its prospective role in immune thrombocytopenia (ITP).ELISA was adopted to measure plasma IL-35, TGF-β and IL-10 levels. The mRNA expression levels of P35 and EBI3 in peripheral blood mononuclear cells (PBMCs) were studied based on real-time quantitative PCR. The correlation between plasma cytokine levels and clinical parameters was analyzed. Significantly lower plasma IL-35 levels were found in active ITP patients compared with those in remission (p = 0.017) and the healthy controls (p < 0.001). In active ITP patients, the plasma IL-35 levels displayed a significantly positive correlation with platelet counts (r = 0.5335, p < 0.0008). Further, P35 mRNA expression levels were lower in patients with active ITP than patients in remission (p = 0.033) and normal controls (p = 0.016).Thus, for the first time, this research reported a dramatically decreased IL-35 levels in ITP patients, suggesting that IL-35 may be involved in the pathogenesis of ITP.     

L-17与自身免疫性疾病关系的研究进展

IL-17是CD4 T细胞亚群Th17分泌的细胞因子。Th17的发育、扩增及分泌IL-17主要受TGF-β、IL-6、IL-15、IL-23等细胞因子的调控。IL-17调节前炎性因子、趋化因子等的产生及分泌,在白细胞的迁移、破骨细胞的活化和骨质的吸收等方面发挥重要作用。研究证实,IL-17在自身免疫性疾病的发生、发展中也具有一定的影响和作用。     

Emerging role of air pollution in autoimmune diseases

Autoimmune diseases (ADs) are a broad spectrum of disorders featured by the body's immune responses being directed against its own tissues, resulting in prolonged inflammation and subsequent tissue damage. Recently, the exposure to ambient air pollution has been implicated in the occurrence and development of ADs. Mechanisms linking air pollution exposures and ADs mainly include systemic inflammation, increased oxidative stress, epigenetic modifications induced by exposures and immune response caused by airway damage. The lung may be an autoimmunity initiation site in autoimmune diseases (ADs). Air pollutants can bind to the Aryl hydrocarbon receptor (AHR) to regulate Th17 and Treg cells. Oxidative stress and inducible bronchus associated lymphoid tissue caused by the pollutants can influence T, B cells, resulting in the production of proinflammatory cytokines. These cytokines stimulate B cell and dendritic cells, resulting in a lot of antibodies and self-reactive T lymphocytes. Moreover, air pollutants may induce epigenetic changes to contribute to ADs. In this review, we will concern the associations between air pollution and immune–inflammatory responses, as well as mechanisms linking air pollution exposure and autoimmunity. In addition, we focus on the potential roles of air pollution in major autoimmune diseases including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), and type 1 diabetes mellitus (T1DM).     

Air pollution in autoimmune rheumatic diseases: A review

Air pollution consists of a heterogeneous mixture of gasses and particles that include carbon monoxide, nitrates, sulfur dioxide, ozone, lead, toxic by-product of tobacco smoke and particulate matter. Oxidative stress and inflammation induced by inhaled pollutants may result in acute and chronic disorders in the respiratory system, as well as contribute to a state of systemic inflammation and autoimmunity. This paper reviews the mechanisms of air contaminants influencing the immune response and autoimmunity, and it focuses on studies of inhaled pollutants triggering and/or exacerbating rheumatic diseases in cities around the world. Remarkably, environmental factors contribute to the onset of autoimmune diseases, especially smoking and occupational exposure to silica in rheumatoid arthritis and systemic lupus erythematosus. Other diseases such as scleroderma may be triggered by the inhalation of chemical solvents, herbicides and silica. Likewise, primary vasculitis associated with anti-neutrophil cytoplasmic antibody (ANCA) may be triggered by silica exposure. Only few studies showed that air pollutants could trigger or exacerbate juvenile idiopathic arthritis and systemic lupus erythematosus. In contrast, no studies of tropospheric pollution triggering inflammatory myopathies and spondyloarthropathies were carried out. In conclusion, air pollution is one of the environmental factors involved in systemic inflammation and autoimmunity. Further studies are needed in order to evaluate air pollutants and their potentially serious effects on autoimmune rheumatic diseases and the mechanisms involved in the onset and the exacerbation of these diseases.     

Bistability in autoimmune diseases

Autoimmune diseases damage host tissue, which, in turn, may trigger a stronger immune response. Systems characterized by such positive feedback loops can display co-existing stable steady states. In a mathematical model of autoimmune disease, one steady state may correspond to the healthy state and another to an autoimmune steady state characterized by widespread tissue damage and immune activation. We show how a triggering event may move the system from the healthy to the autoimmune state and how transient immunosuppressive treatment can move the system back to the healthy state.     

IL-35在机体对HBV感染免疫应答中的调节作用

HBV感染机体后可诱导免疫细胞产生包括白介素-35(IL-35)在内的多种免疫分子.IL-35作为一个新发现的IL-12家族的成员,可以影响多种免疫细胞和免疫分子的产生.目前研究证明,IL-35在乙肝病毒(HBV)感染中具有抑制机体免疫应答的作用,可以诱导机体对HBV的免疫耐受,亦可发挥减轻HBV感染所致肝细胞免疫损伤的作用.文章综述了IL-35的特性及其免疫调控的机制.