IL-33/ST2信号转导系统及其与疾病关系的研究进展

IL-33是近年来发现的IL-1超家族的一员,其特异性受体是ST2,IL-33/ST2信号通路可直接诱导Th2细胞因子的产生,从而影响机体的固有免疫。ST2又以不同的存在形式调节IL-33的生物学作用。IL-33/ST2信号通路在很多疾病发展过程中也起着非常重要的作用。     

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。     

IL-33与人类疾病关系的研究进展

IL-33是近年来发现的一种具有多种生物学功能活性的细胞因子,属于IL-1家族新成员,可作为核内定位分子发挥转录因子的作用,亦可作为一种前炎性细胞因子参与组织特异性免疫病理损伤.IL-33还被认为是细胞坏死后释放的一种“警报素”,在激发免疫系统引起组织损伤或反应中发挥重要作用.近年来证实,IL-33通过与其受体ST2结合,活化胞内核转录因子(NF)-κB等信号通路,参与调节炎症反应、感染性疾病、心血管疾病及肿瘤等多种疾病的发生发展过程.     

非小细胞肺癌患者中IL-33及其受体ST2对Th1/Th2/Th17型细胞因子的影响

为探究IL-33与受体抑癌蛋白2(suppression of tumorigenicity 2,ST2)及相关细胞因子在非小细胞肺癌(non-small cell lung cancer,NSCLC)患者中的作用,收集30例NSCLC患者样本为病例组,同时收集40例健康者为对照组,采用实时荧光定量PCR法和免疫组化法检测NSCLC组织中IL-33和ST2的mRNA与蛋白水平;ELISA检测样本血清中IL-33/可溶性ST2(soluble ST2, sST2)、IFN-γ、IL-4、IL-10和IL-17A的水平;Pearson法分析NSCLC患者血清中IL-33与IL-4、IFN-γ、IL-10、IL-17A的相关性。结果显示,与对照组相比,NSCLC患者病灶组织中IL-33和ST2的mRNA与蛋白水平均显著升高(P0.05);患者血清中IL-33、sST2、IL-10、IL-17A和IL-4的水平显著升高,IFN-γ水平显著降低(P0.05);患者血清中IL-33与IL-4、IL-10的水平呈显著正相关(r=0.65,P0.01;r=0.77,P0.01),与IFN-γ水平呈显著负相关(r=-0.82,P0.01),而与IL-17A的水平不相关。由此,IL-33与受体ST2在NSCLC患者中表达增高可能引起Th1/Th2细胞因子分泌的免疫失衡。     

IL-33/ST2信号途径在免疫调节和肝脏疾病中的研究进展

白细胞介素1( interleukin-1,IL-1)家族是第一个被发现、成员不断被更新的细胞因子家族.到目前为止,IL-1家族有11个成员被发现,分别是IL-1a( IL-1 F1)、IL-1β( IL-1 F2)、IL-1Ra( IL-1F3)、IL-18(IL-1F4)、IL-1F5～10和IL-33( IL-1F11)[1-2].其中,IL-33是最近被发现并受到强烈关注的细胞因子.对于它的发现及其生物学作用经历了一个由基础到临床研究逐步过渡的过程.Tominaga等[3 ]于1989年鉴定出了IL-33特异性受体ST2,证明了ST2是Toll样/IL-1受体(IL-1R)超家族的一个成员,随后发现了ST2的4个亚型.     

IL-33/ST2信号通路在肿瘤发生、发展和抗肿瘤免疫应答中的作用及其机制

近年来,肿瘤免疫治疗逐渐成为恶性肿瘤的前沿疗法。细胞因子IL-33是一种重要的内源性“危险信号”,在肿瘤免疫治疗中显示出潜在的应用价值。IL-33通过与其天然受体肿瘤抑制素2(suppression of tumorigenicity 2,ST2)结合,参与多种生物学效应。但IL-33/ST2信号通路在肿瘤免疫应答中的作用及其机制一直存在争议,目前普遍认为其具有促进肿瘤生长或抑制肿瘤生长的双重作用。随着对IL-33认识的深入,IL-33的临床应用价值更加广泛。该文回顾了IL-33/ST2信号通路对肿瘤发生、发展和调控免疫应答的作用及其机制,及以IL-33/ST2信号轴为靶点的潜在临床应用。     

IL-33与免疫细胞的关系

IL-33是IL-1家族的新成员,在炎性刺激后由多种细胞表达IL-33,并且在细胞溶解过程中释放.IL-33的膜表面受体包括ST2和IL-1受体辅佐蛋白,机体广泛表达ST2,尤其是在Th2型细胞和肥大细胞等免疫细胞中.IL-33通过结合免疫细胞膜表面的ST2将活化信号传递到胞内,经过一系列的信号传递,引起IL-5等免疫因子的释放,起到调节免疫应答等功能.     

IL-33及其受体ST2L在银屑病患者外周血T细胞及皮损组织中的表达北大核心CSCD

目的：研究IL-33及其受体ST2L在银屑病患者外周血T细胞和皮损组织中的表达。方法：采用免疫组织化学法检测寻常型银屑病（PV组）、脓疱型银屑病（PP组）和色素痣切除者[为对照组（CON组）]皮损中IL-33、ST2L的表达和分布。分别采用免疫印迹法和RT-PCR法检测经IL-17A诱导后Jurkat T细胞、HaCat角质形成细胞中IL-33及IL-33 mRNA的表达情况；用同样的方法检测经IL-33诱导后Jurkat T细胞、PV组T细胞、PP组T细胞、CON组T细胞中ST2L及ST2L mRNA表达情况。结果：PV组和PP组患者的皮损中，观察到IL-33及其受体ST2L蛋白在表皮和真皮细胞中均有不同密度的阳性染色。CON组T细胞中表达微量IL-33蛋白，但在银屑病组中，包括PV组和PP组中T细胞有IL-33蛋白明显表达，PP组表达量大于PV组，差异有统计学意义（P<0.05）;IL-33诱导Jurkat T细胞、PV组和PP组患者T细胞表达一定量ST2L蛋白和mRNA，呈剂量依赖性；PV组和PP组中ST2L蛋白表达高于在同一浓度CON组IL-33诱导产生的ST2L水平，差异具有统计学意义（P<0.05）;IL-17A诱导Jurkat T细胞产生IL-33蛋白和mRNA呈一定量效和时效关系；IL-17A诱导HaCat角质形成细胞表达IL-33蛋白和mRNA，呈剂量依赖性，IL-33蛋白主要在HaCat角质形成细胞的细胞核中表达，部分胞质有一定表达，且IL-17A高浓度刺激后，其表达量明显增加。结论：银屑病患者的外周血T细胞和皮损中IL-33及其受体ST2L表达水平明显升高，表明IL-33在银屑病的发生发展中可能发挥重要作用。     

白介素-33的功能作用及研究进展

IL-33是白介素-1(IL-1)家族成员之一，在多种外周组织和中枢神经系统广泛表达。IL-33既可在细胞核中发挥转录作用，亦可分泌到细胞外发挥炎症因子作用。在细胞损伤或病毒感染时，IL-33作为细胞的“警报素”释放，与ST2受体结合，调节机体的自身免疫和炎症反应。同样，IL-33在中枢神经系统疾病也具有重要功能。本文围绕IL-33/ST2的结构和功能，并聚焦于IL-33最新研究进展，旨在探讨IL-33在炎症性和神经系统疾病发生发展中的作用及其可能的治疗前景。     

IL-33/ST2激活人肺成纤维细胞表达纤维黏连蛋白1和1型胶原蛋白参与哮喘气道重塑

目的检测IL-33刺激下人肺成纤维细胞(HLF-1)纤维黏连蛋白1(FN1)及1型胶原蛋白(Col1)的表达。方法选取哮喘组28例,健康对照组25例,ELISA检测血清IL-33的表达;同时对其中8例哮喘患者及8例健康对照者行电子气管镜下气道黏膜活检,HE染色观察哮喘患者气道重塑,免疫组织化学染色观察IL-33在气道黏膜的分布;培养HLF-1人肺成纤维细胞,分别给予不同浓度IL-33细胞因子刺激,通过实时定量PCR和Western blot法分别检测人肺成纤维细胞FN1和Col1的mRNA、蛋白表达。结果 ELISA检测结果显示哮喘病人组血清IL-33表达水平明显高于健康对照组(P0.01);HE染色显示哮喘患者基底膜明显增厚且哮喘患者基底膜厚度与血清IL-33成正相关性(r=0.829,P0.05);免疫组化结果显示IL-33主要来自受损的气道上皮细胞;不同浓度IL-33细胞因子刺激下的HLF-1人肺成纤维细胞FN1、Col1的表达呈浓度依赖性增高(P0.05),丙酸氟替卡松及阻断IL-33受体ST2可以部分抑制FN1和Col1的表达(P0.05)。结论 IL-33/ST2可能通过激活人肺成纤维细胞过度表达FN1和Col1参与哮喘气道重塑。     

IL-33及其与相关疾病关系的研究进展

IL-33是最近发现的一种新IL-1家族细胞因子,可发挥双重作用,作为细胞因子参与调节Th2型机体免疫和炎症反应;同时作为核因子定位于细胞核内,起转录调控作用.IL-33被认为是Th2型免疫反应的关键活化因子,例如在线虫和变态反应疾病中促进Th2细胞、肥大细胞、嗜碱粒细胞、嗜酸性细胞活化释放IL-5、IL-13等Th2...     

Monoclonal antibodies targeting ST2L Domain 1 or Domain 3 differentially modulate IL-33-induced cytokine release by human mast cell and basophilic cell lines

The cell-surface receptor ST2L triggers cytokine release by immune cells upon exposure to its ligand IL-33. To study the effect of ST2L-dependent signaling in different cell types, we generated antagonist antibodies that bind different receptor domains. We sought to characterize their activities in vitro using both transfected cells as well as basophil and mast cell lines that endogenously express the ST2L receptor. We found that antibodies binding Domain 1 versus Domain 3 of ST2L differentially impacted IL-33-induced cytokine release by mast cells but not the basophilic cell line. Analysis of gene expression in each cell type in the presence and absence of the Domain 1 and Domain 3 mAbs revealed distinct signaling pathways triggered in response to IL-33 as well as to each anti-ST2L antibody. We concluded that perturbing the ST2L/IL-33/IL-1RAcP complex using antibodies directed to different domains of ST2L have a cell-type-specific impact on cytokine release, and may indicate the association of additional receptors to the ST2L/IL-33/IL-1RAcP complex in mast cells.     

The enigmatic processing and secretion of interleukin-33

Interleukin-33 (IL-33) is the most attractive novel cytokine identified as an IL-1 family member. IL-33 was first named NF-HEV (nuclear factor from high endothelial venules), as it was known to interact with nuclear chromatin although its exact intracellular functions are still to be clarified. IL-33 is now recognized as the specific ligand for the orphan IL-1 receptor family member ST2 and to be involved in polarization of T cells towards T helper 2 cell phenotype and in activation of mast cells, bosophils, eosinophils and natural killer cells. It is essential for IL-33 to be extracellularly released in order to bind to the ST2 receptor and consequently play a crucial role in inflammatory, infectious and autoimmune diseases. However, like the IL-1 family members, IL-1β and IL-18, IL-33 mRNA is translated without a signal sequence for secretion. Additionally, IL-33 cannot be released by the processing and secretion mechanism shared by IL-1β and IL-18 as IL-33 is not a substrate of caspase-1 and does not require proteolysis for activation. In contrast, IL-33 can be inactivated by apoptotic caspases. Accordingly, IL-33 is proposed to be released as an alarmin from necrotic cells but to be deleted during apoptosis. Besides the known autocrine, paracrine, intracrine, juxtacrine and retrocrine mechanisms of cellular interaction with cytokines, release by necrotic cells is another pathway for a cytokine to display its function, which we suggest might be called ‘necrocrine''. This mini review summarizes recent progress of how IL-33 displays potential immunoregulatory roles with a particular focus on its enigmatic production.     

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.     

电针治疗对实验性自身免疫性脑脊髓炎大鼠体内产生细胞因子的影响

目的 观察电针刺激足三里穴位对实验性自身免疫性脑脊髓炎(EAE)大鼠体内分泌的细胞因子的影响.方法 将免疫大鼠随机分为四组:用完全弗氏佐剂免疫组(CFA组);用MBPB68-86B多肽与完全弗氏佐剂免疫组(EAE组);用MBPB68-86B多肽免疫后的大鼠电针刺激足三里穴位组和用MBPB68-86B多肽免疫后的大鼠电针刺激非穴位组.分别于免疫后第7天、14天和21天采用ELISA方法检测大鼠血浆中IFN-γ、IL-4、IL-17、IL-6和TGF-β细胞因子水平.结果 EA组与EAE组大鼠血浆中IL-4水平有所升高(第14天P=0.027,第21天P=0.36);IFN-γ表达量在第14天EA组明显低于EAE组(P=0.00021);IL-6在三个时间点EA组均明显低于EAE组(P=0.0078,P=0.00047,P=0.00093);IL-17免疫21天,EA组明显低于EAE组(P=0.0012);TGF-β在第7天和第14天EA组明显高于EAE组(P=0.020,P=0.041)结论 电针刺激足三里穴位对EAE大鼠的治疗作用,通过降低炎症细胞因子的产生,促进抑炎细胞因子的产生而发挥作用.     

A role for interleukin-33 in TH2-polarized intestinal inflammation?

Interleukin 33 (IL-33) is a recently discovered cytokine member of the IL-1 superfamily that is widely expressed in fixed tissue cells, including endothelial and epithelial cells. IL-33 induces helper T cells, mast cells, eosinophils, and basophils to produce type-2 cytokines through binding to the ST2/IL-1 receptor accessory protein complex. Recent studies have shown IL-33 to be upregulated in intestinal parasite infection and in epithelial cells and myofibroblasts in ulcerative colitis (UC). The findings point to a role for IL-33 in directing the T(H)2-type immune responses in these types of mucosal inflammation. As the IL-33/ST2 receptor axis can be manipulated by various blocking antibodies, this could be a potential therapeutic target in the future treatment of UC.     

Endogenous IL-33 enhances Th2 cytokine production and T-cell responses during allergic airway inflammation

IL-33 is an IL-1-related cytokine which has been implicated in T(h)2-associated biology and allergic diseases in humans and mice. IL-33 stimulates T(h)2 cells, mast cells, eosinophils, basophils, iNKT cells and circulating CD34(+) stem cells to proliferate and produce pro-allergic cytokines such as IL-5 and IL-13. IL-33 mediates its cytokine effects through a receptor consisting of ST2 and IL-1RAcP. Whereas IL-1RAcP is ubiquitously expressed, ST2 expression is cell-type restricted and determines responsiveness to IL-33. Studies employing ST2-deficient mice have reported variable results on the role of this receptor, and consequently IL-33, with regards to allergic lung inflammation. In this study, we demonstrate that IL-33 is important for allergic lung inflammation. Intra-nasal administration of IL-33 triggered an immediate allergic response in the airways, and more importantly, we show that endogenous IL-33 contributes to airway inflammation and peripheral antigen-specific responses in ovalbumin-induced acute allergic lung inflammation using IL-33-deficient mice. Our results suggest that IL-33 is sufficient and required for severe allergic inflammation in the lung and support the concept of IL-33 as a therapeutic target in allergic lung inflammation.     

The Evolutionary Role of the IL-33/ST2 System in Host Immune Defence

Interleukin (IL)-33 is a recently identified pleiotropic cytokine, which can orchestrate complex innate and adaptive immune responses in immunity and disease. It has been characterized as a cytokine of the IL-1 family and affects a wide range of immune cells by signalling through its receptor ST2L. Accumulating evidence suggests a crucial role of IL-33/ST2 in inducing and modifying host immune responses against a variety of pathogens including parasites, bacteria, viruses and fungi as well as sterile insults of both endogenous and exogenous source. In this review, we endeavour to give a comprehensive overview of the current knowledge about the role of IL-33 and its receptor ST2 in host defence against infections.     

玉屏风散对S180荷瘤小鼠Th1／Th2型细胞因子的影响

目的探讨玉屏风散对荷瘤小鼠Th1／Th2型细胞因子产生的影响。方法采用体外培养S180肉瘤细胞，接种C57BL／6纯系小鼠，建立荷瘤小鼠模型，设正常对照、荷瘤对照及玉屏风散给药组，检测各组脾脏T淋巴细胞增殖能力及Th1（IL-2、IFN-γ）和Th2（IL-4、IL-10）细胞因子产生水平。结果荷瘤组T细胞增殖能力明显下降，Th2型细胞因子IL-10的产生明显增加，与正常对照组比较均有统计学意义（P〈0．01），而IL-4的含量略有增加，但无统计学意义。Th1型细胞因子IL-2及IFN-γ的产生明显减少，与正常对照组比较有统计学意义（P〈0．01，P〈0．05）。玉屏风散给药对T细胞增殖能力及细胞因子的产生有较为明显的调节作用，与荷瘤组比较T细胞增殖能力及IL-2、IFN-γ的产生明显增加（P〈0．01），Th2型细胞因子IL-10的血清含量下降（P〈0．01）．IL-4的含量略有下降，但与荷瘤对照组比较无统计学意义。结论玉屏风散可有效调节荷瘤小鼠的免疫功能，促进荷瘤鼠Th1型细胞因子的产生，有效纠正荷瘤导致Th1／Th2的失衡，增强机体的抗肿瘤免疫功能。