IL-35在免疫相关性疾病中的研究进展

白细胞介素35(interleukin-35,IL-35)是由EBI3和p35形成的IL-12家族新成员。研究发现,IL-35不仅由调节性T(Treg)细胞分泌,还由其他多种免疫细胞分泌。同时研究表明,IL-35在多种免疫相关性疾病中发挥重要的调节作用,其中包括通过抑制Thl7型细胞分化和促进Treg细胞增殖来发挥免疫抑制功能。因此,本综述总结了IL-35的结构和目前在多种疾病中的生物学功能,讨论了IL-35在不同细胞中所用的受体不同,同时探讨了IL-35在多种免疫相关性疾病中产生的机制及调控免疫反应的功能研究。     

IL-23的研究进展

IL 2 3是新近发现的一种细胞因子 ,主要来源于活化的单核巨噬细胞和B细胞。它具有多种生物学功能 ,能促进T细胞尤其是CD4 T细胞增殖 ,促进T细胞、抗原提呈细胞产生IFN γ与IL 12 ,对树突状细胞的共刺激功能起调节作用 ,具有抗肿瘤和抗转移活性 ,而且与自身免疫和炎症反应疾病密切相关。     

IL-17和IL-35水平与甲状腺癌关系的Meta分析

目的 探讨白细胞介素(interleukin,IL)-17和IL-35水平与甲状腺癌的关系.方法 应用计算机检索PubMed、中国知网和万方数据库自200年1月至2016年12月关于IL-17和IL-35水平与甲状腺癌关系的临床对照试验.按纳入和排除标准选择文献,提取数据.采用Stata12.0软件对纳入文献进行Meta分析.结果 纳入文献5篇,样本量409例.与对照组比较甲状腺癌患者IL-17水平明显增加[WMD=6.31, 95%CI(5.89, 6.73)],而IL-35水平明显减低[WMD=-8.52, 95%CI(-9.40, -7.63)],其差异均具有统计学意义(P均<0.05).结论 现有证据表明IL-17和IL-35水平与甲状腺癌的关系密切,其可为甲状腺癌的诊断、治疗和预后提供依据.     

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.     

IL-23研究进展

IL 2 3是新近发现的一种促炎性细胞因子 ,隶属于IL 12分子家族。类似于IL 12 ,IL 2 3是由两种亚单位 (p4 0和p19)通过二硫键形成的异二聚体分子 ,二者的生物学功能也有很多相似之处 ,但并不完全相同 ,提示IL 2 3在维护机体内环境的稳定以及病理条件下免疫系统的激活等方面发挥着独特的生物学作用     

白介素-35的结构及其与疾病关系研究进展

IL-35是CD4+CD25+Treg分泌的抑制性细胞因子。IL-35在抑制效应T细胞增殖、Th17细胞分化和IL-17的合成方面发挥重要作用。研究证实,IL-35在自身免疫性疾病和炎症性疾病的发生、发展中也具有一定的抑制作用。     

冠心病患者血浆IL-35水平的变化及意义

冠状动脉粥样硬化性心脏病(coronary atherosclerotic heart disease,CHD)是动脉粥样硬化(atherosclerosis,AS)性疾病中最常见也是最严重的类型.AS是一种慢性炎症性疾病,往往表现为促炎相关因子活性升高和抗炎细胞与因子活性下降[1].具有抑制免疫活性作用的调节性T细胞(regulatory T cell,Treg)及其自身分泌的抗炎细胞因子IL-10和TGF-β1 对AS有明确的保护作用.Treg分泌一种新型抑制性细胞因子白介素35(IL-35),IL-35具有调节免疫反应、阻止和延缓多种炎症性疾病发生、发展的功能[2].但IL-35在CHD患者外周血中水平的变化及其意义未见报道.本研究检测98例CHD患者和33例正常人血浆中IL-35水平变化,并分析与冠脉病变的关系,探讨IL-35在CHD发病机制中的可能作用.     

IL-17与疾病相关的研究进展

IL-17是目前新发现的主要由CD4 记忆T淋巴细胞、单核细胞等分泌的一种前炎性细胞因子，具有强大的招募中性粒细胞、促进多种细胞释放炎性因子、促进细胞增殖及抑制部分肿瘤生长等多种生物学作用，目前研究发现其与机体多种疾病相关，特别是肺部感染、哮喘、类风湿性关节炎、器官移植、肠道炎症等炎症性疾病关系密切，本文就IL-17在各种疾病中的作用加以综述。     

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.     

Emerging role of IL-35 in inflammatory autoimmune diseases

Interleukin 35 (IL-35) is the recently identified member of the IL-12 family of cytokines and provides the possibility to be a target for new therapies for autoimmune, inflammatory diseases. It is composed of an α chain (p35) and a β chain (EBI3). IL-35 mediates signaling by binding to its receptors, activates subsequent signaling pathways, and therefore, regulates the differentiation, function of T, B cells, macrophages, dendritic cells. Recent findings have shown abnormal expression of IL-35 in inflammatory autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, type 1 diabetes, psoriasis, multiple sclerosis, autoimmune hepatitis, experimental autoimmune uveitis. In addition, functional analysis suggested that IL-35 is critical in the onset and development of these diseases. Therefore, the present study will systematically review what had been occurred regarding IL-35 in inflammatory autoimmune disease. The information collected will help to understand the biologic role of IL-35 in immune cells, and give information about the therapeutic potential of IL-35 in these diseases.     

IL-26的研究进展

IL-26是T淋巴细胞对于疱疹病毒saimiri转染的应答产物之一，属于IL-10细胞因子超家族。它通过IL-26受体（IL-26R，IL-20R1／IL-10R2）的介导而激活STAT1和STAT3，从而发挥生物学活性。从目前的研究现状来看，IL-26可能与多种疾病有关，但还有待于更多的实验研究证实。     

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.     

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.     

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.     

Human placental trophoblasts express the immunosuppressive cytokine IL-35

Studies of maternal–fetal tolerance focus on defining mechanisms for establishment of immunological privilege within the uterus during pregnancy. Fetal trophoblasts play a key role in maternal tolerance, in part through cytokines production. As a novel inhibitory cytokine, IL-35 is produced by Foxp3⁺ regulatory T cells (Tregs) and mediates maximal suppression of Tregs. The purpose of the study is to analyze the expression of IL-35 in first-trimester human placental trophoblasts. IL-35 expression was detected at both protein and mRNA levels by immunohistochemical staining and quantitative real-time PCR method, respectively and secretion of IL-35 was measured by ELISA assay. Our results demonstrated that human trophoblasts constitutively expressed IL-35. Ebi3 and p35 (two subunits of IL-35) mRNA was shown to be co-expressed in trophoblast cells. Moreover, large amounts of secreted IL-35 were detected in the supernatants of trophoblast cells. But we did not detect the constitutive expression of IL-35 in decidual stromal cells. Our findings confirmed for the first time that first-trimester human trophoblast cells expressed and secreted IL-35, which might contribute to their suppressive capacity to maternal immune cells. Therefore, IL-35 may be an important factor of the cytokine network regulating local immune responses during human pregnancy.     

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.     

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.