白细胞介素-18在支气管哮喘中的研究进展

白细胞介素(interleukin,IL)-18是一种特殊的细胞因子,既能诱导Th1型免疫应答,又能诱导Th2型免疫应答,从而参与许多慢性炎症和自身免疫性疾病炎性反应。支气管哮喘是一种Th1/Th2失衡,由多种细胞(嗜酸性粒细胞、T细胞、肥大细胞等)和多种细胞因子(IL-4、IL-5、IL-13等)参与,以支气管壁的结构改变、气道高反应性为特征的肺部慢性炎症性疾病。IL-18在哮喘的不同发病阶段有不同的作用机制,扮演着重要角色。IL-18能诱导γ干扰素形成,从而促进Th1细胞免疫反应,调节Th1/Th2平衡,IL-18还通过上调Treg细胞的生成对哮喘起保护作用。而有些情况下,IL-18及其促分泌的Th1细胞因子又能加重Th2型反应和气道炎症,使哮喘恶化。     

免疫调节剂对哮喘的免疫治疗作用

哮喘是一种慢性气道炎症性疾病,免疫机制是哮喘的重要发病机制之一,研究表明Th细胞是哮喘各种临床表现的重要启动和调控因子。Th1细胞亚群比例失调,即Th1/Th2细胞因子平衡偏移在发病机制中占主导地位。当机体初次接触过敏原时,抗原提呈细胞提呈的抗原和细胞因子共同作用于Th0细胞,Th0细胞接收到信号后可分化为Th1、Th2、Th17或调节性T细胞。活化的辅助性T细胞(主要是Th2细胞)产生白介素(IL)如IL-4、IL-5、IL-9、IL-13等Th2型细胞因子,激活包括肥大细胞在内的固有(Resident)炎性细胞,并从血液中募集淋巴细胞、嗜酸性粒细胞及中性粒细胞等其他炎性细胞,释放各种炎性介     

IL-33及其受体ST2的研究进展

IL-33是IL-1家族的新成员,是炎症反应和免疫偏倚的重要调节因子之一,主要诱导Th2型免疫。IL-33正常情况下存在于细胞核中,作为转录因子发挥作用,当细胞受到损伤时可分泌IL-33至胞外后与受体ST2结合,从而作为细胞因子发挥作用。这一过程对正常细胞生物学功能的发挥和多种疾病的发生发展都密切相关。     

Bach2对Th2细胞内IL-33生物学功能的影响

目的：探讨Bach2与Th2细胞内IL-33生物学功能的关系。方法：构建Bach2基因的条件敲除小鼠(Bach2-CKO小鼠),将Bach2-CKO小鼠与正常小鼠分为两组,IL-33经鼻诱导Th2型免疫应答,对比分析两组小鼠肺部炎症情况;从小鼠脾脏中分离na?ve CD4~+T细胞并诱导分化为Th2细胞;下调(或上调)细胞内Bach2表达后给予IL-33刺激,检测Th2型细胞因子表达。结果：与正常小鼠相比,IL-33显著增加Bach2-CKO小鼠肺组织内炎症细胞浸润、黏液腺分泌以及IL-4、IL-5和IL-13mRNA表达;与正常Th2细胞相比,IL-33更加显著地促进Bach2-/-Th2细胞IL-5和IL-13表达(P<0.01);上调细胞内Bach2表达显著抑制IL-33相关IL-5和IL-13表达(P<0.01)。结论：Bach2参与Th2细胞内IL-33/ST2信号通路调控,可有效抑制该细胞内IL-33的生物学功能。     

IFN-γ/IL-4细胞因子失衡与乙型病毒性肝炎宫内感染的关系

宫内感染是乙型肝炎传播的主要途径之一,机体内HBV清除与1型T辅助细胞/2型T辅助细胞(Th1/Th2)细胞因子有关,通常将γ干扰素(IFN-γ)产生水平作为Th1细胞功能的指标,以白细胞介素4(IL-4)产生水平作为Th2细胞功能的指标,因此,研究IFN-γ/IL-4型细胞因子对阻断乙型肝炎病毒宫内感染具有重要意义。本文就IFN-γ/IL-4细胞因子失衡与乙型肝炎病毒宫内感染关系作一探讨。     

059 IL-13与支气管哮喘

支气管哮喘是由多种细胞特别是肥大细胞、嗜酸性粒细胞和T淋巴细胞参与的慢性气道炎症.哮喘的发生过程中有多种细胞因子参与,白介素-13(IL-13)是近年来新克隆的淋巴因子.IL-13作为Th2型细胞因子成员,具有多种生物学功能.通过激活嗜酸性粒细胞,减少其凋亡,促进IgE分泌等机制,参与哮喘炎症的维持,诱导气道高反应性及小气道结构重建.     

细胞因子诱导支气管上皮细胞表达嗜酸粒细胞趋化因子

Eotaxin和新近发现的Eotaxin-2在支气管上皮细胞中的表达以及Th2型细胞因子的调节作用。以支气管上皮细胞株BEAS-2B细胞为研究对象,通过RT-PCR的方法测定Th2型细胞因子IL-4、IL-13以及促炎症因子TNF-α单独和协同刺激下BEAS-2B细胞Eotaxin和Eotaxin-2的基因表达,通过ELISA方法测定细胞培养上清液中Eotaxin蛋白的表达。EotaxinmRNA在TNF-α刺激12h后表达最高,Th2型细胞因子IL-4和IL-13与TNF-α协同刺激后表达进一步增强,Eotaxin蛋白的表达在协同刺激下也呈剂量和时间依赖性增高(P<0.01)。Eotaxin-2mRNA在TNF-α的刺激下于8h表达最高,IL-4或IL-13与TNF-α的协同刺激也使表达进一步增强,Eotaxin和Eotaxin-2两者基因表达具有相关性(P<0.05)。Th2型细胞因子可与促炎症因子TNF-α协同刺激支气管上皮细胞增强表达嗜酸粒细胞趋化因子Eotaxin和Eotaxin-2,从而吸引嗜酸粒细胞浸润至气道参与哮喘炎症过程。     

IL-18与HBV宫内感染关系的研究进展

乙型肝炎病毒宫内感染的发生发展与机体免疫功能失调密切相关。1型T辅助细胞/2型T辅助细胞（Th1/Th2）细胞因子不平衡应答是HBV感染慢性化的主要机理。IL-18可以通过诱生IFN-γ、IL-2等细胞因子促进Th1应答,从而调节Th1/Th2细胞平衡,因此研究IL-18型细胞因子对阻断乙型肝炎病毒宫内感染具有重要意义,本文就IL-18与HBV宫内感染关系作进一步探讨。     

IL-33及其受体ST2在炎症性肠病中免疫调节作用的研究新进展

IL-33是近年来发现的一种IL-1家族的细胞因子,其受体为ST2.IL-33具有双重作用,既能作为分泌性细胞因子,参与调节Th2型免疫应答,诱导前炎性因子的表达,又能作为核因子,定位于细胞核内,起抑制转录作用,阻遏前炎性基因表达.在慢性炎症性肠病(IBD)患者的肠道组织中可查到该细胞因子的表达.研究IL-33及ST2受体有助于进一步了解IBD发病机制,寻找治疗IBD的新靶点.     

IL-33与皮肤炎症性疾病关系的研究进展

IL-33是IL-1细胞因子超家族的成员,组成性的表达于多种人类组织的细胞上,在皮肤组织细胞上呈现高表达。IL-33的特异性受体是转硫酶同系物(ST2),主要表达在Th2细胞、肥大细胞、巨噬细胞、树突状细胞、NK细胞和自然杀伤性T细胞等免疫细胞表面。IL-33的经典信号途径是通过ST2配体(ST2L)和IL-1受体辅助蛋白(IL-1RAP)组成的异二聚体,将信号转导至细胞内。IL-33是一种双效型的细胞因子,与皮肤多种炎症性疾病密切相关,尤其是银屑病和特应性皮炎,本文对IL-33及其在皮肤相关炎症性疾病的研究进展进行了综述。     

Interleukin-17 and its expanding biological functions

Interleukin-17 (IL-17) and IL-17-producing cells have been shown to play important roles in inflammation and the immune response. IL-17 is believed to be mainly produced by T helper 17 (Th17) cells, a unique helper T-cell subset different from Th1 and Th2 cells. Other subsets of T cells such as γδT and natural killer T (NKT) cells have also been found to produce IL-17 in response to innate stimuli. IL-17 acts as a proinflammatory cytokine that can induce the release of certain chemokines, cytokines, matrix metalloproteinases (MMPs) and antimicrobial peptides from mesenchymal and myeloid cells. This leads to the expansion and accumulation of neutrophils in the innate immune system and links innate and adaptive immunity in vivo. Furthermore, increasing evidence indicates that IL-17 and IL-17-producing cells are involved in the pathogenesis of various diseases such as allergies, autoimmune diseases, allograft transplantation and even malignancy. They may also play protective roles in host defense against infectious diseases and promote induction of cytotoxic T lymphocyte (CTL) responses against cancer. Targeting of the IL-17 axis is under investigation for the treatment of inflammatory disorders.     

The roles of IL-17A in inflammatory immune responses and host defense against pathogens

Summary: T-helper 17 (Th17) cells are a newly discovered CD4⁺ helper T-cell subset that produces interleukin-17A (IL-17A) and IL-17F. IL-17A plays important roles in allergic responses such as delayed-type hypersensitivity, contact hypersensitivity, and allergic airway inflammation. IL-17A promotes inflammation by inducing various proinflammatory cytokines and chemokines, recruiting neutrophils, enhancing antibody production, and activating T cells. IL-17A expression is also augmented in autoimmune diseases such as multiple sclerosis and rheumatoid arthritis. Using mouse models of these diseases, we found that IL-17A plays a central role in their development. IL-6 is required for the development of Th17 cells and tumor necrosis factor functions downstream of IL-17A during the effector phase. IL-1 is important both for developing Th17 cells and eliciting inflammation. Th17 cells, like Th1 and Th2 cells, are involved in host defense against infections, but the contribution of these Th subsets to defense mechanisms differs among pathogens. The roles of IL-17F remain largely unknown. In this review, we introduce how IL-17A/IL-17F are involved in inflammatory immune responses and host defense mechanisms and discuss their relationship with other cytokines in the development of inflammatory and infectious diseases.     

IL-25与免疫相关疾病关系的研究进展

IL-25又称为IL-17E,是细胞因子IL-17家族的成员之一,主要由活化的Th细胞和肥大细胞所分泌。与其他家族成员不同,IL-25能够诱导Th2型细胞因子如IL-4、IL-5和IL-13的产生,介导Th2类免疫应答,还能够影响Th17细胞的分化并调节自身免疫性疾病的发生发展。总之,IL-25在多种免疫性疾病的发生发展中都发挥着重要的作用。     

Type 2 innate immune responses and the natural helper cell

The T helper type 2 (Th2) immune response, characterized by the production of interleukin-4 (IL-4), IL-5 and IL-13, is a critical immune response against helminths invading cutaneous or mucosal sites. It also plays a critical role in the pathophysiology of allergic diseases such as asthma and allergic diarrhoea. The Th2 cytokines are induced soon after helminth infection, even before a pathogen-specific adaptive immune response is established. Recent studies have shed light on such innate Th2 cytokine production by formerly uncharacterized innate immune cells such as natural helper cells capable of producing Th2 cytokines in response to IL-25 and IL-33 independently of adaptive immune responses. These cells produce large amounts of Th2 cytokines, most notably IL-5 and IL-13, leading to eosinophilia and goblet cell hyperplasia. We discuss here the mechanisms of innate production of Th2 cytokines in host immune responses against helminth infection as well as allergic immune responses and the similarities and differences between recently identified Th2-cytokine producing cells.     

IL-33 is a chemoattractant for human Th2 cells

IL-33 is a novel cytokine of the IL-1 family and mediates its biological effect via the receptor ST2, which is selectively expressed on Th2 cells but not Th1 cells. IL-33 drives production of Th2-associated cytokines including IL-5 and IL-13 and thereby promotes defense and pathology in mucosal organs. Cell locomotion is crucial to the induction of an effective immune response. We report here the chemoattraction of Th2 cells by IL-33. Recombinant IL-33 increased the proportion of human Th2 cells, but not Th1 cells, in polarized morphology in vitro and stimulated their subsequent invasion into collagen gels in an IL-33 concentration-dependent manner. Injection of recombinant IL-33 into the footpad of ST2(-/-) mice which had been adoptively transferred with polarized Th2 cells, led to local accumulation of the transferred Th2 cells. These data therefore demonstrate that IL-33 is a selective Th2 chemoattractant associated with the pro-inflammatory property of this novel cytokine.     

The role of the IL-33/IL-1RL1 axis in mast cell and basophil activation in allergic disorders

Interleukin-33 (IL-33) is a recently discovered cytokine that belongs to the IL-1 superfamily and acts as an important regulator in several allergic disorders. It is considered to function as an alarmin, or danger cytokine, that is released upon structural cell damage. IL-33 activates several immune cells, including Th2 cells, mast cells and basophils, following its interaction with a cell surface heterodimer consisting of an IL-1 receptor-related protein ST2 (IL-1RL1) and IL-1 receptor accessory protein (IL-1RAcP). This activation leads to the production of a variety of Th2-like cytokines that mediate allergic-type immune responses. Thus, IL-33 appears to be a double-edged sword because, in addition to its important contribution to host defence, it exacerbates allergic responses, such as allergic rhinitis and asthma. A major purported mechanism of IL-33 in allergy is the activation of mast cells to produce a variety of pro-inflammatory cytokines and chemokines. In this review, we summarize the current knowledge regarding the genetics and physiology of IL-33 and IL-1RL1 and its association with different allergic diseases by focusing on its effects on mast cells and basophils.     

Regulation of defense responses against protozoan infection by interleukin-27 and related cytokines

Cytokine-mediated immunity is crucial in the defense against pathogens. Recently, IL-23 and IL-27 were identified, which along with IL-12 belong to the IL-12 cytokine family. IL-27 is pivotal for the induction of helper T cell (Th) 1 responses while IL-23 is important for the proliferation of memory type Th1 cells. Recent studies revealed that IL-27 also has an anti-inflammatory property. In some protozoan infection, various proinflammatory cytokines were over produced causing lethal inflammatory responses in IL-27 receptor-deficient mice. The anti-inflammatory effect of IL-27 depends, at least partly, on inhibition of the development of Th17 cells, a newly identified Th population that is induced by IL-23 and is characterized by the production of the inflammatogenic cytokine, IL-17. IL-27 thus has a double identity as an initiator and as an attenuator of immune responses and inflammation. With the discoveries of the new IL-12-related cytokines and Th17 cells, Th development is facing a new paradigm.     

Beyond inflammation: airway epithelial cells are at the interface of innate and adaptive immunity

It has become increasingly clear that airway epithelial cells are central participants in innate and adaptive immune responses as well as mucosal inflammation. Epithelial cells produce antimicrobial host defense molecules, proinflammatory cytokines and chemokines in response to activation via pathogen recognition receptors. Recruitment of immune cells including dendritic cells, T cells and B cells into the proximity of epithelium results in the enhancement of adaptive immunity through interactions with epithelial cells. Newly identified epithelial-derived cytokines, including TSLP, IL-33 and BAFF, help to shape the local accumulation and activation of Th2 responses and B cell immunoglobulin production. Epithelial cells are also downstream targets of molecules that activate IL-13R and EGFR and are responsible for mucus production in both protective immune responses and allergic airway inflammatory diseases. Improved understanding of epithelial immune and inflammatory responses will hopefully suggest new strategies for therapeutic intervention.     

The CXCL12/CXCR4 axis is involved in the maintenance of Th2 bias at the maternal/fetal interface in early human pregnancy

The regulatory mechanism of Th2 bias at the maternal/fetal interface remains unclear. In this study, we characterized cytokine production in decidual stromal cells (DSCs), decidual immune cells (DICs) and embryo-derived trophoblast cells, and investigated the regulation of CXCL12/CXCR4 interaction on Th2 bias at the maternal/fetal interface in early human pregnancy. We found differential production of Th1-type and Th2-type cytokines by trophoblasts, DSCs and DICs. The secretion of these cytokines varied in different cell cocultures, conduced to Th2 bias. Flow cytometry showed that coculture of trophoblasts with DSCs and DICs significantly increased IL-4 and IL-10 production in trophoblasts, and IL-10 production in DSCs. However, the coculture of trophoblasts with DSCs and DICs significantly increased interferon (IFN)-γ expression in DSCs, and tumor-necrosis factor (TNF)-α expression in DICs. No change was seen in Th1-type cytokine production in trophoblasts, and in Th2-type cytokine production in DICs in all cocultures. Furthermore, pre-treatment with anti-CXCR4 neutralizing antibody upregulated the production of the Th1-type cytokines IFN-γ and TNF-α, and downregulated the production of the Th2-type cytokines IL-4 and IL-10, in trophoblasts, DSCs, DICs or their cocultures. Interestingly, rhCXCL12 inhibited production of the Th1-type cytokine TNF-α and enhanced the expression of the Th2-type cytokines such as IL-4 and IL-10 in DICs; this effect was abrogated by anti-CXCR4 antibody. Our present study has elucidated the individual contributions of component cells to the shaping of Th2 bias, and uncovered a complicated cross-talk via the CXCL12/CXCR4 signal at the maternal/fetal interface in early human pregnancy.