白介素33在类风湿关节炎中的研究进展

白介素33（interleukin-33,IL-33）是细胞因子白介素1（IL-1）超家族的新成员,其受体为ST2,包括跨模型ST2（ST2L）和可溶性ST2（sST2）两种。IL-33可以通过调节Th2介导的免疫应答,在诸多炎症中起着重要作用,包括类风湿关节炎（rheumatoid arthritis,RA）。IL-33在介导先天免疫反应调节中通过激活肥大细胞来发挥在RA中重要的作用。该文将近年来IL-33在RA动物模型、患者的发病机制中的作用做一简要综述。     

IL-33/ST2信号通路在过敏性疾病中的作用机制及中医药干预机制研究进展

IL-33作为IL-1家族的成员,在免疫及过敏性疾病中发挥重要作用。研究显示,其通过与其受体ST2结合,激活多种炎性细胞及信号通路,在多种疾病中发挥重要作用。本文就IL-33及其受体ST2在免疫及过敏性疾病中的作用机制的研究进展进行综述,并对文献报道的治疗过敏性疾病的中药复方对IL-33/ST2通路的作用机制进行整理分析,以期为临床治疗相关疾病提供依据和方法。     

IL-33／ST2途径：治疗靶标和新型生物标记物

研究表明,白细胞介素-1受体家族成员ST2是炎症反应和自身免疫疾病中的孤儿受体。2005年鉴定出一个新的细胞因子白细胞介素-33（IL-33）,它是ST2的功能配体。IL-33／ST2信号途径参与T-细胞介导的免疫应答,最近又发现其在心血管疾病中具有重要作用。IL-33／ST2信号途径不仅是很有前途的心血管生物标记物,而且是心肌内成纤维细胞-心肌细胞信息交流的新型机制,可能成为预防心力衰竭的治疗靶标。     

可诱导共刺激分子配体的研究进展

可诱导共刺激分子配体(ICOSL)及其受体可诱导共刺激分子(ICOS)在免疫应答和调节中发挥重要作用。ICOSL参与T淋巴细胞和B淋巴细胞的活化,诱导Th1细胞和Th2细胞的细胞因子产生,ICOS/ICOSL共刺激通路在炎症反应性疾病及肿瘤相关疾病中起重要作用。本文对ICOSL的研究进展进行综述,以期提高对多种免疫相关性疾病的认识。     

IL-4、IFN-γ和TGF-β1在支气管哮喘发病过程中的作用

支气管哮喘简称哮喘,是由多种炎性细胞和炎性介质介导的气道慢性炎性疾病,近年来发病率急剧增加,已成为全世界重点关注的疾病之一。辅助性T淋巴细胞亚群Th1/Th2比例和功能失衡是哮喘的主要免疫学发病机制,其中IL-4和IFN-γ在哮喘的发病过程中起着重要作用,并与哮喘的严重程度相关［1］。气道重塑是支气管哮喘的重要病理特征之一,是呼吸道炎性反应反复损伤和修复的结果［2］,转化生长因子-β1（ TGF-β1）通过多种途径参与哮喘气道炎性反应和气道重塑［3］。越来越多的证据表明,细胞因子在哮喘的发生发展中起着重要作用。笔者就近几年有关IL-4、IFN-γ和TGF-β13种重要细胞因子在支气管哮喘发病机制中的研究进展作如下综述。     

以腺苷及其受体信号为靶点的类风湿关节炎疾病和治疗研究进展

类风湿关节炎(RA)是一种慢性自身免疫疾病,目前其发病机制尚未明确,也没有特效药物。新型有效免疫调节药物的发现对RA的有效治疗至关重要。腺苷是一种嘌呤核苷,也是一类重要的免疫调节信号分子,与细胞膜表面的腺苷受体(ARs)结合,ARs为G蛋白偶联腺苷受体有四种亚型,包括A_1AR、A_(2A)AR、A_(2B)AR、A_3AR。被活化的ARs调控促炎细胞因子及抗炎细胞因子释放,从而调节多种免疫细胞功能,参与RA的发生、发展,是RA治疗的潜在靶点。本文围绕腺苷及其受体各亚型在RA发生、发展中作用的研究新进展及针对调节腺苷及受体功能的药物研发新动态进行综述。     

细胞因子在类风湿关节炎发病机制中作用的研究进展

类风湿关节炎（rheumatoid arthritis,RA）是一种病因尚未明确的以滑膜慢性炎症为主的自身免疫性疾病,近年研究发现,细胞因子网络失衡在RA的发病和进展中发挥着重要作用,该病的加重或好转依赖于炎性细胞冈子和调节性细胞因子之间的动态变化。其中TNF-α、IL-1、IL-17、IL-33等在RA滑膜病变中起核心作用,而IL-4、IL-10、TGF-β等细胞因子却可以起到减轻关节损伤的作用。本文将从致炎细胞因子、抑炎细胞因子与RA之间的关系来阐述RA的发病机制。     

血清白介素12、白介素18在Graves病不同病程的变化

Graves病(GD)是一种器官特异性自身免疫性疾病,细胞因子在其发病中起非常重要的调控作用。白介素12(IL-12)及白介素18(IL-18)是Th1相关性细胞因子。有学者报道IL-12及IL-18在GD患者血清中可升高,但对这两者在GD病程不同发展阶段的变化报道还很少。本文报告其在GD不同病程中的变化。     

EBI3在其异源二聚体免疫反应中的作用

EB病毒诱导基因3(Epstein-Barr virus induced gene 3,EBI3)是IL-12家族成员,最初发现于EB病毒感染的B细胞培养上清液,为可溶性细胞因子受体,在体内以同源二聚体、IL-27异源二聚体和IL-35异源二聚体三种形式存在。在免疫应答中,EBI3参与Th1、Th2和Th17细胞的活化与分化,发挥抗感染和抗炎症发生中起着重要的作用。     

抗IL-12/23单克隆抗体Briakinumab

银屑病是一种炎症性免疫介导性疾病,其发病机制虽尚不明确,但有研究表明可能由Th17细胞启动,后者则由白介素（IL）-12和其他通路激活。银屑病存在多种遗传相关性,包括IL-12和IL-23的共有亚单位p40及IL-23受体的缺陷或缺失。     

IL-33 induces both regulatory B cells and regulatory T cells in dextran sulfate sodium-induced colitis

Interleukin (IL)-33 is a member of the IL-1 family. Serum levels of IL-33 are increased in inflammatory bowel diseases (IBD), suggesting that IL-33 is involved in the pathogenesis of IBD, although its role is not clear. In this study, we investigated the role of IL-33 in the regulation of T-helper (Th) cell and B cell responses in mesenteric lymph nodes (MLN) in mice with dextran sulfate sodium (DSS)-induced colitis. Here, we showed that IL-33-treated mice were susceptible to DSS-induced colitis as compared with PBS-treated mice. The production of spontaneous inflammatory cytokines production by macrophages or dendritic cells (DC) in MLN significantly increased, and the responses of Th2, regulatory T cells (Treg) and regulatory B cells (Breg) were markedly upregulated, while Th1 responses were significantly downregulated in MLN of IL-33-treated mice with DSS-induced colitis. Our results demonstrate that IL-33 contributes to the pathogenesis of DSS-induced colitis in mice by promoting Th2 responses, but suppressing Th1 responses, in MLN. Moreover, IL-33 treatment increased Breg and Treg responses in MLN in mice with DSS-induced colitis. Therefore, modulation of IL-33/ST2 signaling is implicated as a novel biological therapy for inflammatory diseases associated with Th1 responses.     

IL-17E在肿瘤中的生物学作用研究进展

IL-17E（又称IL-25）作为近几年来新发现的IL-17家族成员,凭借其独有的结构和功能,不仅介导Th2型免疫反应在过敏性疾病和抗寄生虫感染中发挥重要作用,而且在控制Th1/Th17介导的炎症反应中也有重要的作用。其独有的双重作用机制及其在肿瘤免疫中的作用越来越受到关注。此文就IL-17E和其受体的结构特征、功能特点及其在不同肿瘤中的生物学作用进行综述,以期为IL-17E在肿瘤中相关作用的研究提供参考。     

Targeting IL-33/ST2 signaling: regulation of immune function and analgesia

Introduction: IL-33 signals through ST2 receptor and promotes inflammation by activating downstream pathways culminating in the production of pro-inflammatory mediators such as IL-1β, TNF-α, and IL-6 in an NF-κB-dependent manner. In fact, compelling evidence has demonstrated the importance of IL-33/ST2 in both innate and adaptive immune responses in diseases presenting pain as an important clinical symptom.

Areas covered: IL-33 is a pleiotropic cytokine with varied immune functions. Dysregulation of this pathway has been described as a key step in varied immune responses. Further, IL-33 contributes to peripheral and spinal cord nociceptor neuron sensitization in innate and adaptive inflammatory immune responses as well as in neuropathic and cancer pain. In this sense, targeting IL-33/ST2 signaling is a promising therapeutic approach.

Expert opinion: The modulation of IL-33/ST2 signaling represents a possible approach in regulating immune functions. In addition to immune function, strategies targeting IL-33/ST2 signaling pathway display a favorable preclinical analgesic profile in both acute and chronic models of pain. Therefore, IL-33-targeting therapies represent a potential target for the development of novel analgesic drugs given that IL-33 activates, for instance, neutrophils, mast cells, macrophages, astrocytes, and microglia that are important cells in the induction and maintenance of chronic pain states.     

The IL-33/ST2 pathway: therapeutic target and novel biomarker

For many years, the interleukin-1 receptor family member ST2 was an orphan receptor that was studied in the context of inflammatory and autoimmune disease. However, in 2005, a new cytokine--interleukin-33 (IL-33)--was identified as a functional ligand for ST2. IL-33/ST2 signalling is involved in T-cell mediated immune responses, but more recently, an unanticipated role in cardiovascular disease has been demonstrated. IL-33/ST2 not only represents a promising cardiovascular biomarker but also a novel mechanism of intramyocardial fibroblast-cardiomyocyte communication that may prove to be a therapeutic target for the prevention of heart failure.     

A bis-malonic acid fullerene derivative significantly suppressed IL-33-induced IL-6 expression by inhibiting NF-κB activation

IL-33 functions as a ligand for ST2L, which is mainly expressed in immune cells, including mast cells. IL-33 is a potent inducer of pro-inflammatory cytokines, such as IL-6, and has been implicated in the pathogenesis of allergic inflammatory diseases. Therefore, IL-33 has recently been attracting attention as a new target for the treatment of inflammatory diseases. In the present study, we demonstrated that a water-soluble bis-malonic acid fullerene derivative (C₆₀-dicyclopropane-1,1,1′,1′-tetracarboxylic acid) markedly diminished the IL-33-induced expression of IL-6 in bone marrow-derived mast cells (BMMC). The bis-malonic acid fullerene derivative suppressed the canonical signaling steps required for NF-κB activation such as the degradation of IκBα and nuclear translocation of NF-κB by directly inhibiting the IL-33-induced IKK activation. Although p38 and JNK also contributed to IL-33-induced expression of IL-6, the bis-malonic acid fullerene derivative did not affect their activation. Furthermore, the bis-malonic acid fullerene derivative had no effect on the NF-κB activation pathway induced by TNFα and IL-1. These results suggest that the bis-malonic fullerene derivative has potential as a specific drug for the treatment of IL-33-induced inflammatory diseases by specifically inhibiting the NF-κB activation pathway.     

The regulation of CD4+ T cell immune responses toward Th2 cell development by prostaglandin E2

As an important immune mediator, PGE2 plays an important role in the immune tolerance, autoimmune diseases, immune regulation and tumor immunotolerance. PGE2 is considered to be a promising candidate for the control of the immune diseases. To further understand the immuno-modulating effects of PGE2 on CD4+ T cells, in vitro investigation was conducted in the present study. The results showed that PGE2 inhibited the proliferation of T cells in vitro in a dose-dependent manner. Gene expression profiling showed that 1716 genes were down regulated and 73 genes were up regulated with a change of 1.5 fold. Several signal transduction pathways were involved, such as TNF-α and NF-kB signaling pathway, T cell receptor signaling pathway, IL-2 signaling pathway, and MAPK pathway. The results showed that PGE2 inhibited IFN-γ, TNF-α and IL-4 production by CD4+ T cells 24 h after cell culture. A comparison between IFN-γ and IL-4 production showed that PGE2 enhanced the relative ratio of IL-4 to IFN-γ in CD4+ T cells culture, and regulated CD4+ T cells toward Th2 cell development. The results of the present study indicated that PGE2 has the potential to treat Th1-mediated inflammatory diseases by regulating CD4+ T cells toward Th2 cell immune response.     

Immune deviation strategies in the therapy of psoriasis

The experience with biologicals in currently available animal models suggest that inflammatory autoimmune disease depend on IFN-gamma-producing T helper (Th) cells. Deletion of T cells improves most of these autoimmune diseases but bears the risks of general immunosuppression. Alternatively, selective deviation of the inflammatory, disease-inducing Th cells into an anti-inflammatory Th cell phenotype may be a promising strategy to treat inflammatory autoimmune diseases, such as psoriasis, rheumatoid arthritis, multiple sclerosis or autoimmune diabetes. The common feature of these organ-specific autoimmune diseases is the close association with IFN-gamma-producing Th1 cells, which recognize organ-specific antigens and orchestrate the cells and mediators that ultimately cause the tissue damage. Even though the autoantigens recognized in psoriasis remain enigmatic, it has been the first Th1-mediated autoimmune disease successfully treated in humans by immune deviation. The basis of such an immune intervention therapy has been established in experimental mice with model diseases of multiple sclerosis, rheumatoid arthritis or autoimmune diabetes. In all these autoimmune diseases clinical improvement was associated with the skewing of IFN-gamma producing autoantigen-specific Th1 cells into an IL-4 dominated Th2 phenotype. Such Th2 cells are still reactive to the autoantigen but provide a different cytokine pattern. The most powerful cytokines capable of inducing anti-inflammatory Th2 cells are IL-4 itself or IL-11. Interestingly, another agent that has been used for decades in the therapy of psoriasis in some European countries, fumaric acid esters (FAE), seems also to induce immune deviation. This review focuses on the potential immune deviating strategies based on the use of IL-4, IL-11 or FAE in the therapy of psoriasis, the effects of these agents on the immune system, potential risks and future perspectives for therapeutic intervention by immune deviation replacing immunosuppression.     

Lentivirus expressing soluble ST2 alleviates bleomycin-induced pulmonary fibrosis in mice

It has been shown that the expression of ST2, a receptor of interleukin (IL)-33, is elevated in the lungs of idiopathic pulmonary fibrosis patients and bleomycin-induced mouse models, however its contribution to the development of pulmonary fibrosis has yet to be tested. In the present study, we treated mice by intranasal instillation of lentivirus expressing soluble ST2 and evaluated lung inflammation and fibrosis in the bleomycin-induced pulmonary fibrosis mouse model. We found that ST2 lentivirus treatment significantly improved survival rate and reduced weight loss compared with controls treated with empty lentivirus. Furthermore, ST2 treatment profoundly attenuated the pulmonary inflammatory cell infiltration and fibrotic changes. Finally, ST2 treatment markedly lowered the levels of IL-4, IL-6, IL-13, IL-33, monocyte chemoattractant protein-1, and transforming growth factor-β1, whereas it increased the levels of interferon-γ in bronchoalveolar lavage fluid. The results indicate that ST2 might prevent bleomycin-induced pulmonary fibrosis possibly through downregulating proinflammatory and profibrotic mediators. This study suggests that lentivirus expressing soluble ST2 might represent an effective therapeutic approach in the treatment of pulmonary fibrotic diseases.     

Boosting interleukin-10 production: therapeutic effects and mechanisms

More than forty cytokines have been extensively researched on the molecular structure, cell signaling and transduction pathway. With respect to cytokine-regulating therapy in immunological imbalance however, the reported results are conflicting because of the pleiotropic functions and the intricate interactions of the cytokine network. In this review, we outline the observations on interleukin-10 (IL-10) upregulatory therapy. Despite varying opinions on its therapeutic effects for different disorders, IL-10 has been considered a potential anti-inflammatory cytokine. Numerous studies support the view that IL-10 shows a strong suppressive effect on Th1 lymphocytes, antigen presenting cells and the production of inflammatory mediators. It is also noticeable that recent research has revealed the relationship between IL-10 induced antigen specific regulatory CD4+ T cells and antigen specific immune tolerance. This specific regulation was mediated in part through IL-10 secretion, because anti-IL-10 treatment reverted the inhibitory effect of regulatory T cell clones. In different models, these cells were shown to inhibit both Th1 and Th2-type inflammatory responses through the secretion of IL-10. With the presence of IL-10, regulatory T cells may induce peripheral immune tolerance. Exogenous administration, transgenic expression and endogenous stimulative agents of IL-10 have been used for a variety of inflammatory diseases, autoimmune diseases and allograft rejection in patients and experimental models. A therapeutic intervention with drug inducing endogenous IL-10 may be more practical than an exogenous administration of IL-10 with transient effect. Although further investigation on gene regulation of IL-10 is necessary, increasing studies have been reported concerning the attempt to develop the agents, which could promote endogenous IL-10 production for the treatment of immunological disorders and inflammatory diseases. With some unclear mechanisms, these agents have strongly upregulated IL-10 production in vitro or in vivo. Reported IL-10 upregulatory agents have shown promising prospects for remission of autoimmune diseases and inflammatory diseases and have even induced antigen specific immune tolerance. It is interesting that the IL-10 upregulatory effect of several traditional immunosuppressive drugs has been detected, e.g. glucocorticoid, which is considered "not more as an immunosuppressive drug but an immune modulating agent". Approximately twenty IL-10 upregulatory agents as instances are described in the present review. In addition, their therapeutic effects in various diseases are discussed.