白细胞介素-1家族细胞因子研究进展

随着老龄化时代的到来,各种自身免疫性疾病和肿瘤性疾病更加频繁发生,给人类的生命健康和生活质量带来了影响,其中白细胞介素-1(interleukin-1, IL-1)家族成员在这些疾病中起着重要作用。目前,对IL-1家族的研究发展迅速,已鉴定了11种细胞因子和10种受体,其生物学功能、与疾病的关系及应用越来越受到各国科学家的青睐。现对IL-1家族细胞因子、受体、信号通路和生物学功能作一概述,并展望IL-1家族在药物研发和临床治疗方面的应用前景。     

IL-25在支气管哮喘中的作用

白介素25(Interleukin-25,IL-25)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。IL-25能够诱导释放Th2型细胞因子IL-4、IL-5、IL-13,炎性细胞因子IL-6,Th1型趋化因子CXCL10、CXCL9、CCL5的产生,导致嗜酸性粒细胞的浸润,在支气管哮喘的发病中起重要作用,本文就此作一综述。     

细胞因子信号转导的负性调节因子SOCS—1的研究进展

SOCS是新近发现的一类与细胞因子JAK-STAT信号转导途径有关的负性调节因子。目前SOCS家族的成员已达16个之多,该因子能抑制IL-6、IFNγ、IL-2、GH等细胞因子的多种信号转导途径,不仅对JAK-STAT信号途径有负性调控作用,而且还参与其它信号途径的调节,其功能涉及正常组织的分化和器官的发育,因此已为学术界所关注。SOCS-1为该家族中含SH2结构域的SOCS成员之一,本文着重对其分子的结构、负性调节机制及其生物学功能作一综述。     

白介素-17家族细胞因子的研究进展

白介素-17(interleukin-17,IL-17)细胞因子家族含有6个成员,分别是IL-17A(简称IL-17)、IL-17B、IL-17C、IL-17D、IL-17E(也称IL-25)以及IL-17F。IL-17A是该家族中目前研究得最清楚的成员,它可以诱导抗菌肽和炎症性基因的表达,在宿主防御病原微生物如细菌和真菌等的感染中发挥着重要作用,同时也参与多种自身免疫病的炎症性发病病理。IL-17A及其受体的阻断性抗体在牛皮癣和类风湿性关节炎等自身免疫病的临床治疗试验中取得很好的疗效。IL-25诱导Th2相关基因的表达,在过敏反应和宿主抵抗寄生虫感染中发挥重要作用。近年来研究发现,IL-17C也参与宿主抵抗病原菌感染和自身免疫病病理,而IL-17细胞因子家族也参与肿瘤的发生和发展。尽管人们对IL-17A的信号转导机制有了一定的了解,但该家族中其他成员的功能机制还不清楚。因此,深入研究IL-17家族细胞因子的功能与分子机制将为相关疾病,如自身免疫病、感染性疾病、过敏性疾病和肿瘤等的治疗提供重要的理论基础和分子靶标。     

白介素-6细胞因子家族新成员：心肌营养素-1

心肌营养素-1(cardiotrophin-1, CT-1)是一个新发现的白介素-6家族细胞因子,小鼠CT-1的mRNA长约1.4 kb,编码蛋白由203个氨基酸组成,以gp130和LIFR为受体.CT-1对心肌细胞既有肥大诱导作用,又有保护作用;能改变交感神经元的递质表型,促进多巴胺神经元、睫状神经元和运动神经元的存活;还能抑制骨髓白血病细胞M1的生长;诱导肝细胞急性相反应;小鼠腹腔注射给药可增加血小板、红细胞记数和血红蛋白浓度.     

IL-1及家族成员在心肌炎中的作用研究

心肌炎是多种因素引起心肌局限性或弥漫性的炎症病变,近年来许多专家学者对该病进行了大量的研究,但是它的发病机制一直尚未明确。随着心肌炎动物模型试验的基础研究与临床诊疗的不断深入,目前认为心肌炎的发病主要与病毒损伤心肌细胞、免疫机制有关,在此过程中细胞因子IL-1及其家族成员起着重要的作用,本文就IL-1及家族成员在心肌炎的作用机制的研究进展综述如下。     

HLA-DQB1~*02、03基因及IFN-γ、IL-4与广西壮、瑶族肝癌家族聚集性的相关性

本研究探讨HLA-DQB1~*02、03等位基因及细胞因子IFN-γ和IL-4与广西壮、瑶族肝癌家庭聚集性的相关性。将来自肝癌高发区,民族为瑶族的肝癌高发家族成员、无癌家族成员各40例及民族为壮族的肝癌高发家族成员、无癌家族成员各48例作为研究对象(采用相同性别,年龄(±5岁)配对方法),采集研究对象外周血并提取全血DNA,采用PCR-SSP技术检测受试者的HLA-DQB1~*02和HLA-DQB1~*03等位基因,IFN-γ及IL-4细胞因子表达水平采用ELISA法检测。结果发现,HLA-DQB1~*02、03基因在壮族肝癌高发家族成员组的表达频率均低于无癌家族成员组(p0.05);HLA-DQB1~*02基因在瑶族肝癌高发家族成员组的表达频率高于无癌家族组(p=0.002),HLA-DQB1~*03在两组间的表达频率无明显差异(p0.05)。广西壮、瑶族人群HLA-DQB1~*02、03基因在乙肝病毒感染组及非感染组中的表达频率比较无显著性差异(p0.05)。壮、瑶族肝癌高发家族成员组IL-4平均表达水平均高于无癌家族成员组,肝癌高发家族成员组IFN-γ平均表达水平均低于无癌家族成员组,差异具有统计学意义(p0.05)。广西壮、瑶族人群中HLA-DQB1~*02基因阳性和阴性成员的IL-4平均表达水平无明显差异(p0.05)。广西壮族人群中HLA-DQB1~*03基因阳性成员的IFN-γ平均表达水平高于HLA-DQB1~*03阴性成员(p=0.011),HLA-DQB1~*03阳性和阴性成员的IL-4平均表达水平无明显差异(p0.05)。本课题得出结论,HLA-DQB1~*02、03基因与广西壮、瑶族肝癌家庭聚集性有关,但存在较大的民族差异;细胞因子IFN-γ及IL-4的表达水平失衡可能是广西壮、瑶族肝癌家族聚集性的危险因素。HLA-DQB1~*03基因导致广西壮族肝癌家族聚集性的发生可能是通过影响IFN-γ的表达水平来实现的。     

关于IL-10抗炎机制的研究

IL-10属于细胞因子中的干扰素家族,研究发现内源性和外源性的IL-10均能在转录水平上强烈抑制IL-1、IL-6、IL-8肿瘤坏死因子-α(TNF-α)、GM-CSF、G-CSF的合成.近十年来,研究认为IL-10主要是通过抑制IKK的激活或NF-κB的DNA结合能力,从而抑制NF-κB启动相关前炎症因子基因的转录.但同时,国外也报道过IL-10抑制炎症细胞因子如TNF-α的合成可能与NF-κB无关,而与如AP-1,细胞因子信号抑制子-3(SOCS-3)等其他蛋白相关.另一方面,最近随着对NOD家族成员NOD2及其同源异构体的深入研究,有证据表明IL-10对NF-κB的作用可能不仅仅局限在IKK(IκB的激酶)及其下游的水平上,而在上游也会造成影响.     

IL-17家族与哮喘

支气管哮喘(bronchial asthma,简称哮喘)是一种常见的慢性气道炎症性疾病,急性发作可危及生命。研究表明,细胞因子白介素17(interleukin-17,IL-17)家族成员在哮喘的发病过程中发挥着重要的作用,其中IL-17A、IL-17F和IL-17E与哮喘密切相关,是目前的研究热点。现对IL-17家族不同成员与哮喘发病机制的相关研究进展作一综述。     

J Immunol:IL-36 gamma能够缓解肠道炎症反应

正克罗恩氏病与溃疡性结肠炎是两类临床上常见的炎症反应(immune bowel disease),主要表现为对肠道微生物异常的免疫反应。IL-1家族的细胞因子在炎症反应部位表达量都会上调,并促进炎症的恶化。然而,缺乏IL-1beta或IL-18的小鼠却表现出对DSS诱导的肠炎更为敏感的特性。因此,IL-1家族的蛋白对肠炎的发病具有复杂的调控作用。之前的研究证明IL-36家族的蛋白从属于IL-1蛋白家族,而对于这一类蛋白在肠炎中的作用却很少有研究。最近,来自佐治亚州立大学的Timothy L.Denning在《jounral of immunology》杂志上发表文章揭示了细胞因子IL-36 gamma在     

Cardiotrophin-1: Expression in experimental myocardial infarction and potential role in post-MI wound healing

Cardiotrophin-1 (CT-1), a member of the IL-6 family of cytokines, has been shown to be elevated in the serum of patients with ischemic heart disease and valvular heart disease, and induces cardiomyocyte hypertrophy in vitro. We investigated expression of CT-1 in post-MI rat heart and the effect of CT-1 on cultured primary adult rat cardiac fibroblasts. Elevated CT-1 expression was observed in the infarct zone at 24 h and continued through 2, 4 and 8 weeks post-MI, compared to sham-operated animals. CT-1 induced rapid phosphorylation of Jak1, Jak2, STAT1, STAT3, p42/44 MAPK and Akt in cultured adult cardiac fibroblasts. CT-1 induced cardiac fibroblast protein synthesis and proliferation. Protein and DNA synthesis were dependent on activation of Jak/STAT, MEK1/2, PI3K and Src pathways as evidenced by decreased ³H-leucine and ³H-thymidine incorporation after pretreatment with AG490, PD98059, LY294002 and genistein respectively. Furthermore, CT-1 treatment increased procollagen-1-carboxypropeptide (P1CP) synthesis, a marker of mature collagen synthesis. CT-1 induced cell migration of rat cardiac fibroblasts. Our results suggest that CT-1, as expressed in post-MI heart, may play an important role in infarct scar formation and ongoing remodeling of the scar. CT-1 was able to initiate each of the processes considered important in the formation of infarct scar including cardiac fibroblast migration as well as fibroblast proliferation and collagen synthesis. Further work is required to determine factors that induce CT-1 expression and interplay with other mediators of cardiac infarct wound healing in the setting of acute cardiac ischemia and chronic post-MI heart failure.     

Regulation of noradrenergic function by inflammatory cytokines and depolarization

Although the sympathetic neurons innervating the heart are exposed to the inflammatory cytokines cardiotrophin-1 (CT-1), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFalpha) after myocardial infarction, the effects of these cytokines on noradrenergic function are not well understood. We used cultured sympathetic neurons to investigate the effects of these cytokines on catecholamine content, the tyrosine hydroxylase co-factor, tetrahydrobiopterin (BH4), and norepinephrine (NE) uptake. CT-1, but not IL-6 or TNFalpha, suppressed NE uptake and catecholamines in these neurons, whereas CT-1 and, to a lesser extent, IL-6 decreased BH4 content. CT-1 exerted these effects by decreasing tyrosine hydroxylase, GTP cyclohydrolase (GCH) and NE transporter mRNAs, while IL-6 lowered only GCH mRNA. The neurons innervating the heart are also activated by the central nervous system after myocardial infarction. We examined the combined effect of depolarization and cytokines on noradrenergic function. In CT-1-treated cells, depolarization caused a small increase in BH4 and NE uptake, and a large increase in catecholamines. These changes were accompanied by increased TH, GCH and NE transporter mRNAs. CT-1 and depolarization regulate expression of noradrenergic properties in an opposing manner, and the combined treatment results in elevated cellular catecholamines and decreased NE uptake relative to control cells.     

The heart is a source of circulating cardiotrophin-1 in humans

Cardiotrophin-1 (CT-1) is a new member of the interleukin (IL)-6 family of cytokines and one of the endogenous ligands for gp130 signaling pathways in the heart, which has potent hypertrophic and survival effects on cardiac myocytes. However, the clinical significance of CT-1 is poorly understood, mainly because there is no widely applicable specific and sensitive assay system for measuring plasma levels of circulating CT-1. We therefore developed a competitive radioimmunoassay (RIA) for human CT-1 with rabbit antiserum recognizing the N-terminus region of human CT-1 and using recombinant human CT-1 as a calibrator. The assay displays no cross-reactivities with any of the IL-6 family of cytokines including IL-11, leukemia inhibitory factor, ciliary neurotrophic factor, and oncostatin M. The lower detection limit in buffer was found to be 43 fmol/ml, and the working range was 120-8300 fmol/ml (CV < 15%). This RIA directly recognizes CT-1-like immunoreactivity in human plasma with a mean value of 571 +/- 75 fmol/ml (mean +/- SD) in healthy volunteers. The RIA coupled with gel filtration chromatographic analyses showed that the major molecular form of circulating CT-1 corresponds to recombinant full-length human CT-1. Moreover, there is a significant increase in the plasma CT-1 concentration from the aorta and coronary sinus, which clearly indicates that the heart secretes CT-1 via the coronary sinus into the peripheral circulation. This RIA should serve as a powerful tool for investigating the clinical significance of CT-1.     

IN VIVO EFFECTS OF CARDIOTROPHIN-1

Cardiotrophin-1 (CT-1) is a recently discovered cytokine that was isolated based on its ability to induce cardiac myocyte hypertrophy in vitro. In this study, the effects of chronic administration of CT-1 to mice (0.5 or 2 μg by intraperitoneal injection, twice a day for 14 days) were determined. A dose-dependent increase in both the heart weight and ventricular weight to body ratios was observed in the treated groups. The body weights of the animals were unaffected. These results indicate that CT-1 can induce cardiac hypertrophy in vivo. CT-1 was not specific for the heart, however. It stimulated the growth of the liver, kidney, and spleen, and caused atrophy of the thymus. CT-1 administration also increased the platelet counts by 70%, with no change in mean platelet volume. Red blood cell counts were increased in the treated animals, and there was a concomitant increase in haemoglobin concentration. Thus, CT-1 has a broad spectrum of biological activities in vivo. This observation is consistent with previous in-vitro findings showing that the mRNA for CT-1 is expressed in several tissues, and that CT-1 can function through binding to the leukaemia inhibitory factor (LIF) receptor and signalling through the gp130 pathway.     

Increased expression of IL-6 and LIF in the hypertrophied left ventricle of TGR(mRen2)27 and SHR rats

Cytokines from the interleukin-6 (IL-6) family have been reported to play an important synergistic role with angiotensin II in the development of pathological cardiac hypertrophy. Whether their expression pattern changes in vivo, in an angiotensin II-dependent hypertrophied myocardium has not been reported. In this study, we addressed that issue using two animal models of angiotensin II-dependent cardiac hypertrophy. Heterozygous transgenic TGR(mRen2)27 (TGR) with an overactive cardiac renin angiotensin system and the closely related spontaneously hypertensive rats (SHR) were compared to their respective control rats. The mRNA levels of IL-6, leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF) and cardiotrophin-1 (CT-1) as well as their receptor subunits, glycoprotein 130 (gp130), IL-6 receptor (IL-6R), LIFR, and CNTFR, were measured by semi-quantitative RT-PCR. The protein levels of IL-6, LIF and CT-1 were investigated by western blot. TGR and SHR both displayed significant over expression of mRNA and protein levels for IL-6 and LIF. In TGR, the increased level of LIF was accompanied by a decrease in mRNA levels for LIFR and CNTFR. In SHR, a higher level of mRNA IL-6R was observed. By contrast, the mRNA and protein levels for CT-1 and the mRNA level for gp130 did not vary in these two models. These findings suggest that IL-6 and LIF, but not CT-1, contribute to angiotensin II-dependent left ventricular hypertrophy in the two hypertensive rat models, TGR(mRen2)27 and SHR. (Mol Cell Biochem 269: 95–101, 2005)     

Cardiotrophin-1 stimulates intercellular adhesion molecule-1 and monocyte chemoattractant protein-1 in human aortic endothelial cells

Intercellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1) play critical roles in mediating monocyte adhesion to the vascular endothelium and monocyte migration into the subendothelial regions of the vessels. Inasmuch as cardiotrophin-1 (CT-1), an IL-6-type cytokine, was expressed in human atherosclerotic plaque, we examined whether CT-1 induces monocyte adhesion and migration by stimulating gene and protein expressions of ICAM-1 and MCP-1 in human aortic endothelial cells (HAECs). Immunocytochemistry revealed that CT-1 increased intensity of ICAM-1 and MCP-1 immunoreactivity in HAECs. Adhesion assay and chemotaxis assay revealed that CT-1 increased human monocytic THP-1 cell adhesion to HAECs and promoted chemotaxis in THP-1 cells, which were attenuated by anti-ICAM-1 and anti-MCP-1 antibody, respectively. Western blot analysis showed that CT-1 increased phosphorylation of ERK1/2 MAP kinase, p38 MAP kinase, and Akt and that their inhibitors, PD-98059, SB-203580, and LY-294002, respectively, inhibited phosphorylation. RNase protection assay and ELISA demonstrated that CT-1 increased gene and protein expressions of ICAM-1 and MCP-1. EMSA revealed that CT-1 enhanced NF-kappaB DNA-binding activity. CT-1-mediated upregulation of ICAM-1 and MCP-1 was suppressed by PD-98059, SB-203580, LY-294002, and parthenolide. The present study demonstrates that CT-1 promotes monocyte adhesion and migration by stimulating ICAM-1 and MCP-1 through mechanisms that involve ERK1/2 MAP kinase, p38 MAP kinase, phosphatidylinositol 3-kinase, and NF-kappaB pathways and suggests that CT-1 plays an important role in the pathophysiology of vascular inflammation and atherosclerosis.