白介素-33在疾病中的作用

白介素-33(IL-33)是近年来新发现的IL-1家族的新成员,通过结合其受体ST2诱导Th2型细胞因子的产生。IL-33既可以调节Th2型免疫反应、刺激肥大细胞产生前炎性因子,又可以作为核因子调控基因转录。IL-33在血管性疾病、变态反应性疾病、自身免疫性疾病和炎症性疾病中均发挥重要作用。对IL-33功能及机制的研究将有助于进一步了解这些疾病的致病机制,为疾病治疗提供新的策略。     

IL-33／ST2信号通路在疾病中作用的研究进展

IL-33是在2005年发现的一个多功能细胞因子,属于IL-1家族新成员。IL-33通过受体ST2活化NF-KB和MAPK信号通路,促进Th2细胞因子的产生,在多种疾病的发生发展过程中起着重要的作用。     

白介素1受体样1蛋白ST2与肿瘤相关研究进展

白介素1受体样1蛋白ST2(interleukin 1 receptor-like 1)属于TOLL/IL-1受体超家族成员,主要功能型ST2L蛋白由胞内结构域、跨膜结构域和3个细胞外免疫球蛋白样结构域组成。IL-33/ST2信号通路参与机体多种炎性免疫反应,ST2在变态反应性疾病、自身免疫性疾病和心血管性疾病等中发挥了重要作用,近年来研究发现ST2在胃癌、乳腺癌、肝癌等多种肿瘤组织高表达,且与肿瘤的发生和侵袭转移密切相关,其主要机制与影响肿瘤免疫微环境及表达于肿瘤细胞直接影响细胞的生物学行为有关。本文主要就ST2的结构功能及与肿瘤等疾病的关系做一综述。     

白介素-33与炎症

白介素-33（interleukin-33,IL-33）是最近发现的一种前炎症细胞因子,它结合IL-1受体家族成员ST2,活化NF-κB和MAPK信号通路,促进Th2细胞因子的产生,参与多种炎症与免疫反应过程。本文就IL-33的分子结构、编码蛋白、产生及调节、受体信号与生物学活性等作综述。     

白介素-33与炎症

自介紊-33(interleukin.33,IL-33)是最近发现的一种前炎症细胞因子,它结合IL-1受体家族成员ST2,活化NF-w.B和MAPK信号通路,促进Th2细胞因子的产生,参与多种炎症与免疫反应过程.本文就IL-33的分子结构、编码蛋白、产生及调节,受体信号与生物学活性等作综述.     

IL-33通过活化巨噬细胞NF-κB信号通路参与低氧性肺动脉高压的发生发展

目的探讨IL-33/ST2应答轴是否通过激活巨噬细胞NF-κB通路促进低氧性肺动脉高压(hypoxic pulmonary hypertension,HPH)的发生、发展。方法采用野生型(WT)、IL-33转基因(Il33 Tg)小鼠和St2基因敲除(St2-/-)小鼠制备HPH小鼠模型,采集小鼠支气管肺泡灌洗液(bronchoalveolar lavage fluid,BALF)和肺组织标本;进行小鼠BALF总细胞和分类计数;用免疫荧光和免疫组化法检测IL-33、ST2在小鼠肺组织的表达水平和MAC-2+巨噬细胞聚集;用ELISA检测肺组织匀浆中的细胞因子含量;用免疫印迹(Western blot)检测转录因子NF-κB在模型鼠肺组织及体外IL-33刺激的小鼠巨噬细胞系RAW264.7的表达水平。结果 IL-33、ST2在HPH模型小鼠肺组织中表达上调并伴有MAC-2+巨噬细胞增加;Il33 Tg模型鼠肺部以巨噬细胞为主的炎性细胞浸润;低氧可诱导WT小鼠肺组织表达促炎因子IL-1β和巨噬细胞趋化蛋白(monocyte chemotactic protein 1,MCP-1),而St2基因缺失则下调上述细胞因子表达;低氧亦可诱导上调NF-κB在WT小鼠肺组织表达,而St2基因缺失则可抑制低氧诱导NF-κB的表达。体外实验显示IL-33能上调巨噬细胞NF-κB的表达。结论低氧可促进IL-33/ST2表达增强,进而诱导巨噬细胞内NF-κB通路的激活,导致促炎细胞因子MCP-1、IL-1β的产生,加重炎症反应并间接引起肺动脉血管重塑参与HPH的发生、发展。     

miR-487b在改善慢性心力衰竭中的作用机制

为了考察miR-487b在慢性心力衰竭发病过程中的作用及机制,本研究检测了miR-487b在慢性心力衰竭患者中的表达情况,通过冠状动脉左前降支结扎建立大鼠心力衰竭模型,并通过转染miR-487b模拟物和miR-487b抑制剂来调控其表达。研究发现,慢性心力衰竭患者心肌组织中mir-487b的表达水平显著低于健康人(p0.05)。此外,慢性心力衰竭模型大鼠心肌组织中miR-487b的表达也显著下调(p0.05)。上调miR-487b则有效抑制了慢性心力衰竭大鼠心肌细胞肥大,减少了胶原纤维和炎症细胞浸润程度(p0.05)。上调miR-487b还有效减少了心肌细胞凋亡(p0.05)。上调miR-487b则可显著升高大鼠心肌组织中SOD水平并降低MDA水平。采用ELISA法检测慢性心力衰竭患者和健康人血清中IL-33和ST2的水平,发现慢性心力衰竭患者和大鼠中的IL-33和ST2的水平均显著升高。此外,上调miR-487b可显著抑制IL-33和ST2mRNA和蛋白的表达。本研究表明miR-487b在慢性心力衰竭患者和大鼠中均显著下调;上调miR-487b的表达可显著改善慢性心力衰竭大鼠的心脏功能,抑制心肌纤维化和细胞凋亡,提高抗氧化能力;miR-487b可能通过抑制IL-33/ST2信号通路来发挥心脏保护作用。     

白细胞介素-27与疾病关系的研究进展

IL-27由p28(IL-12p35相关多肽)和EBI3(IL-12p40相关蛋白)组成,主要是由抗原呈递细胞产生;其受体是由WSX-1/TCCR(T细胞细胞因子受体)和gp130组成。初步研究表明IL-27可能在炎症性疾病、寄生虫感染、自身免疫性疾病、抗肿瘤作用等方面发挥作用。     

银杏酮酯滴丸联合美托洛尔对冠心病不稳定型心绞痛患者心肌酶指标、氧化应激和外周血IL-33/ST2信号通路的影响

摘要 目的：观察银杏酮酯滴丸联合美托洛尔对冠心病不稳定型心绞痛（UAP）患者心肌酶指标、氧化应激和外周血白介素-33（IL-33）/生长刺激表达基因2蛋白（ST2）信号通路的影响。方法：选取我院2020年1月~2021年12月期间收治的UAP患者70例,根据随机数字表法分为对照组（美托洛尔治疗,35例）和联合组（银杏酮酯滴丸联合美托洛尔治疗,35例）,对比两组疗效、心绞痛改善情况、心肌酶指标、氧化应激及外周血IL-33/ST2信号通路相关指标,记录不良反应发生情况。结果：联合组的临床总有效率（88.57%）高于对照组（68.57%）,差异有统计学意义（P<0.05）。治疗1个月后,联合组的心绞痛发作次数少于对照组,心绞痛发作持续时间短于对照组（P<0.05）。治疗1个月后,联合组血清肌酸激酶同工酶（CK-MB）、乳酸脱氢酶（LDH）、肌酸激酶（CK）、心肌肌钙蛋白（cTnI）低于对照组（P<0.05）。治疗1个月后,联合组血清丙二醛（MDA）水平低于对照组,血清超氧化物歧化酶（SOD）、总抗氧化能力（T-AOC）水平高于对照组（P<0.05）。治疗1个月后,联合组IL-33、ST2信使核糖核酸（mRNA）相对表达量低于对照组（P<0.05）。两组不良反应发生率组间对比无统计学差异（P>0.05）。结论：银杏酮酯滴丸联合美托洛尔治疗UAP患者,可促进症状改善,减轻心肌损伤和氧化应激,作用机制可能与调节IL-33/ST2信号通路有关。     

P2X7受体与炎性细胞因子

P2X7受体是嘌呤受体中功能独特的一个亚型,为ATP控制的离子通道,在单核细胞、巨噬细胞、中性粒细胞中高表达,被ATP激活后导致K＋外流和Ca^2＋内流、非选择性膜孔形成,启动一系列信号途径如炎症小体NALP3的活化,丝裂原蛋白激酶途径激活NF-κB增强炎性细胞因子转录,ROS和氮介质的产生,介导IL-1β、IL-6、IL-18、TNF-α、MIP-2、CCL2、HMGB1等多种炎性细胞因子的释放,参与炎症的发生发展,与真菌感染及阿尔茨海默病、类风湿性关节炎、哮喘等炎症性疾病密切相关.     

Soluble ST2 suppresses the effect of interleukin-33 on lung type 2 innate lymphoid cells

Type 2 innate lymphoid cells (ILC2) in lungs produce interleukin (IL)-5 and IL-13 in response to IL-33 and may contribute to the development of allergic diseases such as asthma. However, little is known about negative regulators and effective inhibitors controlling ILC2 function. Here, we show that soluble ST2, a member of the IL-1 receptor family, suppresses the effect of IL-33 on lung ILC2 in vitro. Stimulation with IL-33 to naïve ILC2 induced morphological change and promoted cell proliferation. In addition, IL-33 upregulated expression of cell surface molecules including IL-33 receptor and induced production of IL-5 and IL-13, but not IL-4. Pretreatment with soluble ST2 suppressed IL-33-mediated responses of ILC2. The results suggest that soluble ST2 acts as a decoy receptor for IL-33 and protects ILC2 from IL-33 stimulation.     

Reconstitution of ST2 (IL-1R4) specific for IL-33 activity; no suppression by IL-1Ra though a common chain IL-1R3 (IL-1RAcP) shared with IL-1

Interleukin-33 (IL-33) receptors are composed of ST2 (also known as IL-1R4), a ligand binding chain, and IL-1 receptor accessory protein (IL-1RAcP, also known as IL-1R3), a signal transducing chain. IL-1R3 is a common receptor for IL-1α, and IL-1β, IL-33, and three IL-36 isoforms. A549 human lung epithelial cells are highly sensitive to IL-1α and IL-1β but not respond to IL-33. The lack of responsiveness to IL-33 is due to ST2 expression. ST2 was stably transfected into A549 cells to reconstitute its activity. RT-PCR and FACS analysis confirmed ST2 expression on the cell surface of A549/ST2 cells. Upon IL-33 stimulation, A549/ST2 cells induced IL-8 and IL-6 production in a dose dependent manner while A549/mock cells remained unresponsive. There was no difference in IL-1α and IL-1β activity in A549/ST2 cells compared to A549/mock cells despite the fact that IL-33 shares IL-1R3 with IL-1α/β. IL-33 activated inflammatory signaling molecules in a time- and dose-dependent manner. Anti-ST2 antibody and soluble recombinant ST2-Fc abolished IL-33-induced IL-6 and IL-8 production in A549/ST2 cells but the IL-1 receptor antagonist failed to block IL-33-induced cytokines. This result demonstrates for the first time the reconstitution of ST2 in A549 human lung epithelial cell line and verified its function in IL-33-mediated cytokine production and signal transduction.     

KU812 cells provide a novel in vitro model of the human IL-33/ST2L axis: Functional responses and identification of signaling pathways

Activation of interleukin-1 family receptor ST2L by its ligand interleukin-33 (IL-33) is an important component in inflammatory responses. Peripheral blood basophils, recognized as major effector cells in allergic inflammation that play a role in both innate and adaptive immunity, are activated by IL-33 through ST2L. However, studies are challenging due to the paucity of this cell population, representing less than 1% of peripheral blood leukocytes. We identified a basophil-like chronic myelogenous leukemia cell line, KU812, that constitutively expresses ST2L and demonstrates functional responses to IL-33 stimulation. IL-33 induced production of multiple inflammatory mediators in KU812 cells that were blocked by anti-ST2L and anti-IL-33 antibodies. The interaction of IL-33 and ST2L activated NF-κB, JNK, and p38 MAPK, but not ERK1/2 signaling pathways. Studies using pharmacological inhibitors to IKK-2 and MAP kinases revealed that one of the functional responses, IL-33-induced IL-13 production, was regulated through NF-κB, but not JNK or p38 MAPK signaling. The requirement of NF-κB was confirmed by IKK-2 knockdown using shRNA. KU812 represents the first human cell line-based in vitro model of the IL-33/ST2L axis and provides a valuable tool to aid in understanding the mechanism and significance of IL-33 and ST2L interaction and function.     

The IL-1 receptor accessory protein (AcP) is required for IL-33 signaling and soluble AcP enhances the ability of soluble ST2 to inhibit IL-33

Interleukin (IL)-33 (or IL-1F11) was recently identified as a ligand for the orphan IL-1 receptor family member T1/ST2 (ST2). IL-33 belongs to the IL-1 cytokine family and, upon binding to ST2, induces intracellular signals similar to those utilized by IL-1. The effects of other IL-1 family cytokines are mediated by their binding to a specific receptor and the recruitment of a co-receptor required for elicitation of signaling. The aim of this study was to characterize the co-receptor involved in IL-33 signaling. Immunoprecipitation confirmed that IL-33 specifically binds ST2 and revealed that cellular IL-1 receptor accessory protein (AcP) associates with ST2 in a ligand-dependent manner. Receptor binding measurements demonstrated that the affinity of mouse (m)IL-33 for ST2 is increased by 4-fold in presence of AcP. IL-33 dose-dependently stimulated IL-6 secretion from wild-type (WT) mast cells, while no effect of IL-33 was observed with mast cells derived from AcP-deficient mice. Finally, soluble (s)ST2-Fc and sAcP-Fc acted synergistically to inhibit IL-33 activity. These observations identify AcP as a shared co-receptor within the IL-1 family that is essential for IL-33 signaling and suggest a novel role for sAcP in modulating the activity of IL-33.     

ST2 and IL-33 in pregnancy and pre-eclampsia

Normal pregnancy is associated with a mild systemic inflammatory response and an immune bias towards type 2 cytokine production, whereas pre-eclampsia is characterized by a more intense inflammatory response, associated with endothelial dysfunction and a type 1 cytokine dominance. Interleukin (IL)-33 is a newly described member of the IL-1 family, which binds its receptor ST2L to induce type 2 cytokines. A soluble variant of ST2 (sST2) acts as a decoy receptor to regulate the activity of IL-33. In this study circulating IL-33 and sST2 were measured in each trimester of normal pregnancy and in women with pre-eclampsia. While IL-33 did not change throughout normal pregnancy, or between non-pregnant, normal pregnant or pre-eclamptic women, sST2 was significantly altered. sST2 was increased in the third trimester of normal pregnancy (p<0.001) and was further increased in pre-eclampsia (p<0.001). This increase was seen prior to the onset of disease (p<0.01). Pre-eclampsia is a disease caused by placental derived factors, and we show that IL-33 and ST2 can be detected in lysates from both normal and pre-eclampsia placentas. ST2, but not IL-33, was identified on the syncytiotrophoblast layer, whereas IL-33 was expressed on perivascular tissue. In an in vitro placental perfusion model, sST2 was secreted by the placenta into the 'maternal' eluate, and placental explants treated with pro-inflammatory cytokines or subjected to hypoxia/reperfusion injury release more sST2, suggesting the origin of at least some of the increased amounts of circulating sST2 in pre-eclamptic women is the placenta. These results suggest that sST2 may play a significant role in pregnancies complicated by pre-eclampsia and increased sST2 could contribute to the type 1 bias seen in this disorder.     

Involvement of GSK-3β in attenuation of the cardioprotective effect of ischemic preconditioning in diabetic rat heart

ST2 gene products that are members of IL-1 receptor family are expressed in various cells such as growth-stimulated fibroblasts and Th2 helper T-cells, and recently, IL-33, which belongs to IL-1 family, was identified as the ligand for ST2L, the receptor type product of the ST2 gene. Subsequently, IL-33 and ST2L have been reported to be involved in Th2 immunity and inflammation, however, their functions on non-immunological cells are still obscure. Among non-immunological adhesive cells, vascular endothelial cells were reported to express both ST2 gene products and IL-33, therefore, we investigated the expression manner of the ST2 gene in vascular endothelial cells and the effect of IL-33 on endothelial cells. ST2 gene was expressed in each of the vascular endothelial cell types tested, and the expression was growth-dependent and down-regulated when the cells were differentiated to form vascular structures on the extracellular membrane matrix. IL-33 scarcely affected the growth and tube formation of the endothelial cells, but induced IL-6 and IL-8 secretion from endothelial cells with the rapid activation of extracellular signal-regulated kinase (ERK) 1/2, so IL-33 is supposed to involve in inflammatory reaction of vascular endothelial cells through its receptor, ST2L.     

IL-1 receptor accessory protein and ST2 comprise the IL-33 receptor complex

IL-33 (IL-1F11) is a recently described member of the IL-1 family of cytokines that stimulates the generation of cells, cytokines, and Igs characteristic of a type 2 immune response. IL-33 mediates signal transduction through ST2, a receptor expressed on Th2 and mast cells. In this study, we demonstrate that IL-33 and ST2 form a complex with IL-1R accessory protein (IL-1RAcP), a signaling receptor subunit that is also a member of the IL-1R complex. Additionally, IL-1RAcP is required for IL-33-induced in vivo effects, and IL-33-mediated signal transduction can be inhibited by dominant-negative IL-1RAcP. The implications of this shared usage of IL-1RAcP by IL-1(alpha and beta) and IL-33 are discussed.