趋化因子CXCL9/Mig的研究进展

趋化因子CXCL9又称为mig,即monokine induced by IFN-γ(IFN-γ诱导的单核因子),是趋化因子CXC亚族的一员,体内主要由IFN-γ刺激的巨噬细胞和神经胶质细胞产生,体外则可由内皮细胞、粒细胞等在IFN-γ和TLR配体协同作用下产生。CXCL9的受体CXCR3为七次跨膜的G蛋白偶联受体。CXCL9对激活的T淋巴细胞和肿瘤浸润淋巴细胞具有趋化作用,但是对粒细胞和单核细胞没有作用。本文主要就CXCL9的结构与生化特征,其在免疫、移植排斥、肿瘤治疗等方面所起的作用,进行了较为系统的综述。     

新发现的CXCL16趋化因子及其受体

一种新的免疫系统分子——由入侵部位的防御性免疫细胞产生的趋化因子CXCLl6。这是迄今为止所发现的第二种可以膜结合方式合成的趋化因子。它属于CXC家族,同时具有CC家族和Cx3C家族(如Fractalkine)趋化因子的特征,它包含跨膜区和粘蛋白(mucin)样结构,以膜结合型和分泌型两种形式存在,主要表达于APC表面。其受体为BONZ0／CXCR6／STRL33／TYMSR的“孤儿受体”,该受体也是SIV／HIV的辅助受体,主要表达于Thl细胞、NK细胞和激活的CD8^ T细胞。CXCL16／BONZ0可能在效应T细胞的迁移、APC和CD8T细胞的相互作用、细胞免疫应答和炎症反应以及胸腺细胞的发育中发挥十分重要的作用。     

趋化因子及趋化因子受体3在自身免疫疾病中的作用

人体在防御和清除入侵病原体等异物时,有一种使白细胞趋集的功能,有一些低分子量的物质能引起这种功能称之为趋化剂或趋化因子。这些小蛋白因其有定向细胞趋化作用而得名。经研究表明,趋化因子受体3（CXCR3）趋化因子可能在自身免疫内分泌疾病中起到致病作用。此外,血清中CXCR3趋化因子的判定可能辅助检测免疫活性。CXCR3和优先参与趋化Th1细胞的因子。该受体连接的趋化因子10（CXCL10）不仅参与白细胞募集,还诱导T细胞增殖的异源体和抗原的刺激。趋化因子10正调节Th1细胞产物并且负调节Th2细胞的产物。免疫反应纤维结合素（INF）产物可增强特异的炎症反应。当被激活或者发现炎症和肿瘤细胞后趋化因子受体3-B在内皮细胞中表达并且其结合的趋化因子10,趋化因子9和趋化因子11激活后产生血管抑制作用。     

人早孕滋养细胞分泌趋化因子CXCL16促进自身增殖和侵袭

本文探讨趋化因子CXCL16在细胞滋养细胞的分泌特征,以及其促进滋养细胞增殖和侵袭的生物学作用。采用原代培养人早孕滋养细胞,ELISA法检测不同种植密度培养12、24、36、48、60、 72、100h上清液中CXCL16分泌水平;[3H]TdR掺入法分析外源性CXCL16刺激后滋养细胞的增殖效应;matrigel侵袭试验分析外源性CXCL16处理后滋养细胞的侵袭性。结果表明原代培养的人早孕滋养细胞可持续分泌趋化因子CXCL16,在最初培养的48h分泌旺盛,培养至100h仍可见CX- CL16分泌;rhCXCL16浓度达100ng/ml时能够明显促进体外培养的滋养细胞增殖效应:rhCXCL16 浓度达10ng/ml时能明显促进滋养细胞的侵袭能力。实验证明人早孕滋养细胞分泌趋化因子CX- CL16,并以自分泌方式促进滋养细胞的增殖和侵袭,可能在胎盘形成和绒毛外滋养细胞的入侵中发挥重要作用。     

趋化因子CXCL1在肿瘤中的作用

趋化因子及其受体在许多生物学过程(如炎症发生、血管生成等)中起重要的作用。趋化因子CXCL1是单亚基趋药性细胞因子,该蛋白主要通过特异性结合G蛋白耦联受体CXCR2,在多种肿瘤的生长、增殖、转移和侵袭以及血管新生中起重要调控作用。该文重点阐述了趋化因子CXC亚家族成员CXCL1在肿瘤中的功能,并对其上游调控因子进行分析,深入探讨了CXCL1与肿瘤的相互关系。     

血管内皮细胞内质网应激

内质网是调控细胞内膜型/分泌型蛋白质合成、钙稳态和细胞凋亡的重要细胞器,多种因素影响内质网稳态、触发内质网应激。适当的内质网应激通过激活未折叠蛋白反应促进内质网紊乱的恢复,但过度内质网应激触发内质网相关凋亡途径,参与多种疾病的发生。血管内皮细胞具有高度发达的内质网,对内质网应激非常敏感,本文综述血管内皮细胞内质网应激反应及其在血管损伤相关疾病中的作用。     

SDF-1/CXCR4在肿瘤信号转导中作用的分子机制

CXC趋化因子受体4(CXCR4)是最主要的趋化因子受体之一,在多种类型细胞中均有表达,包括淋巴细胞、造血干细胞、内皮细胞和肿瘤细胞。CXCR4与其配体——基质细胞衍生因子1(SDF-1)(也称CXCL12)结合,能介导多种与细胞趋化、细胞存活或增殖相关信号传导通路。CXCR4与SDF-1轴涉及肿瘤的恶性演进、血管生成、转移和存活。因此,阻断CXCR4与SDF-1轴及下游信号通路成为相关治疗的分子靶标。     

CXCR7 的生物学功能及其在肿瘤发生发展中的 作用研究进展

趋化因子受体是一类G 蛋白偶联的7 次跨膜受体,其与配体结合能参与调控多种生理和病理学过程。以往,CXCR4 一直被认为 是趋化因子CXCL12 的唯一受体。然而近年来的研究表明CXCL12 能与另一种新受体CXCR7 结合,并在调控肿瘤转移、血管生成和细 胞粘附等方面起着重要作用,CXCR7 由此成为肿瘤治疗的潜在靶点。介绍CXCR7 的结构、生物学功能以及CXCR7 在肿瘤发生发展中 的作用。     

间日疟原虫感染患者T细胞应答相关趋化因子水平的检测

T细胞介导的细胞免疫应答和体液免疫应答对控制疟原虫红内期感染至关重要。免疫细胞的募集和功能调节受到不同趋化因子的调控。进一步寻找招募T细胞的关键性趋化因子将为针对性调控抗疟免疫应答类型提供有效靶点。通过收集并检测中缅边境地区间日疟原虫感染患者血浆中T细胞应答相关的趋化因子水平,并比较CD4~+T细胞和CD8~+T细胞不同表达水平患者的相应趋化因子表达,发现CXCL9、CXCL10、CXCL11、CXCL13、CCL13和CCL1在间日疟急性感染期均显著升高,CXCL10和CXCL13水平与患者的年龄呈正相关,特别是CXCL10对CD4~+T细胞的募集调控可能起到关键性作用。     

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。     

CXC chemokine ligand 16 promotes integrin-mediated adhesion of liver-infiltrating lymphocytes to cholangiocytes and hepatocytes within the inflamed human liver

Lymphocyte recruitment to the liver is critical for viral clearance in acute hepatitis and in the pathogenesis of chronic inflammatory liver disease when persistent chronic inflammation leads to fibrosis and cirrhosis. Chemokines regulate leukocyte recruitment and positioning in tissues and are thus critical regulators of chronic inflammation. The chemokine CXCL16, which is found in liver tissue, exists in a transmembrane as well as soluble form, providing a potential mechanism for localization to particular structures. We studied the role of CXCL16 and its receptor CXCR6 in lymphocyte recruitment and retention in the liver. A higher proportion of CXCR6(+) T cells was detected in blood of hepatitis C virus patients compared with healthy subjects, and in chronic inflammatory liver disease >60% of intrahepatic T cells expressed CXCR6, including CD4, CD8, and CD56(+) T cells compared with <30% in matched blood samples. CXCR6(+) lymphocytes were found in association with CXCL16(+) bile ducts in portal tracts and with hepatocytes at sites of interface hepatitis. Analysis of CXCL16 expression and subcellular distribution in cultured human cholangiocytes, sinusoidal endothelial cells, and hepatocytes revealed that all three cell types expressed CXCL16, with the strongest staining seen on cholangiocytes. CXCL16 on the cholangiocyte membrane was able to support lymphocyte adhesion by triggering conformational activation of beta(1) integrins and binding to VCAM-1. Thus, CXCL16 can promote lymphocyte adhesion to epithelial cells and may function to attract and retain effector cells that promote biliary and hepatocyte destruction in inflammatory liver disease.     

CXCL16 in kidney and cardiovascular injury

CXC chemokine ligand 16 (CXCL16) is a CXC soluble chemokine, an adhesion molecule and a cell surface scavenger receptor. CXCL16 regulates inflammation, tissue injury and fibrosis. Parenchymal renal cells, vascular wall cells, leukocytes and platelets express and/or release CXCL16 under the regulation of inflammatory mediators. CXCL16 expression is increased in experimental and human nephropathies. Targeting CXCL16 protected from experimental glomerular injury or interstitial fibrosis. Conflicting results were reported for experimental cardiovascular injury. High circulating CXCL16 levels are associated to human kidney and cardiovascular disease and urinary CXCL16 may increase in kidney injury. In conclusion, mounting evidence suggests a role of CXCL16 in kidney and cardiovascular disease. However, a better understanding is still required before exploring CXCL16 targeting in the clinic.     

Cutting edge: SR-PSOX/CXC chemokine ligand 16 mediates bacterial phagocytosis by APCs through its chemokine domain

SR-PSOX and CXC chemokine ligand (CXCL)16, which were originally identified as a scavenger receptor and a transmembrane-type chemokine, respectively, are indicated to be identical. In this study, we demonstrate that membrane-bound SR-PSOX/CXCL16 mediates adhesion and phagocytosis of both Gram-negative and Gram-positive bacteria. Importantly, our prepared anti-SR-PSOX mAb, which suppressed chemotactic activity of SR-PSOX, significantly inhibited bacterial phagocytosis by human APCs including dendritic cells. Various scavenger receptor ligands inhibited the bacterial phagocytosis of SR-PSOX. In addition, the recognition specificity for bacteria was determined by only the chemokine domain of SR-PSOX/CXCL16. Thus, SR-PSOX/CXCL16 may play an important role in facilitating uptake of various pathogens and chemotaxis of T and NKT cells by APCs through its chemokine domain.     

The chemokine and scavenger receptor CXCL16/SR-PSOX is expressed in human vascular smooth muscle cells and is induced by interferon gamma

Atherosclerosis is an inflammatory disease that is characterised by the involvement of chemokines that are important for the recruitment of leukocytes and scavenger receptors that mediate foam cell formation. Several cytokines are involved in the regulation of chemokines and scavenger receptors in atherosclerosis. CXCL16 is a chemokine and scavenger receptor and found in macrophages in human atherosclerotic lesions. Using double-labelled immunohistochemistry, we identified that smooth muscle cells in human lesions express CXCL16. We then analysed the effects of IFN-gamma, TNF-alpha, IL-12, IL-15, IL-18, and LPS on CXCL16 expression in cultured aortic smooth muscle cells. IFN-gamma was the most potent CXCL16 inducer and increased mRNA, soluble form, membrane form, and total cellular levels of CXCL16. The IFN-gamma induction of CXCL16 was also associated with increased uptake of oxLDL into these cells. Taken together, smooth muscle cells express CXCL16 in atherosclerotic lesions, which may play a role in the attraction of T cells to atherosclerotic lesions and contribute to the cellular internalisation of modified LDL.     

Critical roles of CXC chemokine ligand 16/scavenger receptor that binds phosphatidylserine and oxidized lipoprotein in the pathogenesis of both acute and adoptive transfer experimental autoimmune encephalomyelitis

The scavenger receptor that binds phosphatidylserine and oxidized lipoprotein (SR-PSOX)/CXCL16 is a chemokine expressed on macrophages and dendritic cells, while its receptor expresses on T and NK T cells. We investigated the role of SR-PSOX/CXCL16 on acute and adoptive experimental autoimmune encephalomyelitis (EAE), which is Th1-polarized T cell-mediated autoimmune disease of the CNS. Administration of mAb against SR-PSOX/CXCL16 around the primary immunization decreased disease incidence of acute EAE with associated reduced infiltration of mononuclear cells into the CNS. Its administration was also shown to inhibit elevation of serum IFN-gamma level at primary immune response, as well as subsequent generation of Ag-specific T cells. In adoptive transfer EAE, treatment of recipient mice with anti-SR-PSOX/CXCL16 mAb also induced not only decreased clinical disease incidence, but also diminished traffic of mononuclear cells into the CNS. In addition, histopathological analyses showed that clinical development of EAE correlates well with expression of SR-PSOX/CXCL16 in the CNS. All the results show that SR-PSOX/CXCL16 plays important roles in EAE by supporting generation of Ag-specific T cells, as well as recruitment of inflammatory mononuclear cells into the CNS.     

Involvement of CXCR3-associated chemokines in MHV-3 induced fulminant hepatic failure

The role of chemokines in murine hepatitis virus strain 3 (MHV-3) induced fulminant hepatic failure (FHF) is not well defined. In this study, we investigated the role of the CXC chemokine receptor 3 (CXCR3)-associated chemokine [monokine induced by IFN-gamma (Mig/CXCL9) and interferon-gamma-inducible protein 10 (IP-10/CXCL10)] in the recruitment of intrahepatic lymphocytes and subsequent fulminant hepatic failure induced by MHV-3. Balb/cJ mice (6–8 weeks, female) were intraperitioneally injected with 100 PFU MHV-3.The proportions and numbers of T cells and NK cells as well as the expression of CXCR3 on T cells and NK cells in the liver, spleen and blood were analyzed by flow cytometry. The hepatic mRNA level of the CXCR3-associated chemokines (CXCL9 and CXCL10) was detected by realtime PCR. A transwell migration assay was used to assess the chemotactic effect of MHV-3-infected hepatocytes on the splenic lymphocytes. Following MHV-3 infection, the number of hepatic NK cells and T cells and the frequencies of hepatic NK cells and T cells expressing CXCR3 increased markedly; however, in the spleen and peripheral blood, they both decreased significantly. Moreover, the hepatic mRNAs levels of CXCL9 and CXCL10 were significantly elevated post infection. The transwell migration assay demonstrated that MHV-3-infected hepatocytes have the capacity to attract and recruit the splenic NK cells and T cells, and CXCL10 plays a key role in lymphocyte mobilization from the spleen. These results suggest that the CXCR3-associated chemokines (CXCL9 and CXCL10) may play an important role in the recruitment of intrahepatic lymphocytes and subsequent necroinflammation and hepatic failure in MHV-3 infection.     

Expression cloning of the STRL33/BONZO/TYMSTRligand reveals elements of CC, CXC, and CX3C chemokines

STRL33/BONZO/TYMSTR is an orphan chemokine and HIV/SIV coreceptor receptor that is expressed on activated T lymphocytes. We describe an expression cloning strategy whereby we isolated a novel chemokine, which we name CXCL16. CXCL16 is an alpha (CXC) chemokine but also has characteristics of CC chemokines and a structure similar to fractalkine (neurotactin) in having a transmembrane region and a chemokine domain suspended by a mucin-like stalk. A recombinant version of CXCL16 fails to mediate chemotaxis to all known chemokine receptor transfectants tested but does mediate robust chemotaxis, high affinity binding, and calcium mobilization to Bonzo receptor transfectants, indicating that this is a unique receptor ligand interaction. In vitro polarized T cell subsets including Th1, Th2, and Tr1 cells express functional Bonzo, suggesting expression of this receptor in chronic inflammation, which we further verified by demonstration of CXCL16-mediated migration of tonsil-derived CD4(+) T lymphocytes. CXCL16 is expressed on the surface of APCs including subsets of CD19(+) B cells and CD14(+) monocyte/macrophages, and functional CXCL16 is also shed from macrophages. The combination of unique structural features of both Bonzo and CXCL16 suggest that this interaction may represent a new class of ligands for this receptor family. Additionally, this chemokine might play a unique dual role of attracting activated lymphocyte subsets during inflammation as well as facilitating immune responses via cell-cell contact.     

The membrane-bound chemokine CXCL16 expressed on follicle-associated epithelium and M cells mediates lympho-epithelial interaction in GALT

The recently identified CXCL16 has dual functions as a transmembrane adhesion molecule and a soluble chemokine. In this study we found that CXCL16 mRNA and protein were expressed constitutively on the follicle-associated epithelium covering Peyer's patches (PPs), isolated lymphoid follicles, and cecal patches, but minimally on the villous epithelium in the murine gastrointestinal tract. The CXCL16 receptor CXCR6/Bonzo was constitutively expressed on subpopulations of CD4+ and CD8+ T cells isolated from PPs. The expression of CXCR6/Bonzo on the PP T cells was up-regulated after stimulation with anti-CD3 and anti-CD28 mAbs. The activated PP T cells showed chemotactic migration in response to the soluble N-terminal chemokine domain of CXCL16. Furthermore, the activated PP T cells selectively adhered to cells expressing murine CXCL16. To determine the physiological role of CXCL16 in GALT, we first carefully analyzed T cell distribution in PPs. T cells localized not only in the interfollicular region but also at a lesser frequency in the subepithelial dome (SED) and in the germinal center of lymphoid follicles. Consistently, the majority of the adoptive transferred activated T cells migrated into the SED and the interfollicular region. However, the neutralization of CXCL16 specifically reduced the migration of the adoptive, transferred, activated T cells into the SED of PPs. These data suggest that CXCL16 expressed on the follicle-associated epithelium plays an important role in the recruitment and retention of activated T cells in the SED and should, at least partially, be responsible for lymphocyte compartmentalization in GALT.     

Recruitment and proliferation of T lymphocytes is supported by IFNgamma- and TNFalpha-activated human osteoblasts: Involvement of CD54 (ICAM-1) and CD106 (VCAM-1) adhesion molecules and CXCR3 chemokine receptor

The mechanism by which osteoblasts (OB) interact and modulate the phenotype and proliferation of T lymphocytes during inflammation is not well known. The effects of two regulatory cytokines, TNFalpha and IFNgamma, on the expression of CD54 (ICAM-1) and CD106 (VCAM-1) adhesion molecules and the CXCR3 ligands (CXCL9, CXCL10, CXCL11), were assessed in a primary culture of human OB by real-time PCR, flow cytometry, and immunohistochemistry. In addition, we functionally evaluated the recruitment and proliferation of T lymphocytes grown with resting or stimulated OB. According to the present data IFNgamma, either alone or in combination with TNFalpha, significantly up-regulates the expression of CD54 and CD106 and induces the expression and release of CXCL9, CXCL10, CXCL11 in OB. The supernatant of TNFalpha- and IFNgamma-activated OB induces the recruitment of T lymphocytes more significantly than stimulation by CXCR3 ligands. T lymphocyte proliferation is significantly enhanced by direct contact with TNFalpha- and IFNgamma-activated OB or by incubation with the supernatant of TNFalpha- and IFNgamma-activated OB. Blocking experiments with anti-CD11a, anti-CD49d, anti-CXCR3, and Bordetella pertussis toxin demonstrate that adhesion molecules and the CXCR3 chemokine receptor play a key role in the proliferation of T lymphocytes. The present study demonstrates the involvement of adhesion molecules (CD11a and CD49d) and chemokine receptor (CXCR3) in the mechanism by which OB recruit, interact, and modulate T lymphocyte proliferation under inflammatory conditions.     

Enhanced expression and shedding of the transmembrane chemokine CXCL16 by reactive astrocytes and glioma cells

The transmembrane chemokine CXCL16 is expressed by dendritic and vascular cells and mediates chemotaxis and adhesion of activated T cells via the chemokine receptor CXCR6/Bonzo. Here we describe the expression and shedding of this chemokine by glioma cells in situ and in vitro. By quantitative RT-PCR and immunohistochemistry, we show that CXCL16 is highly expressed in human gliomas, while expression in normal brain is low and mainly restricted to brain vascular endothelial cells. In cultivated human glioma cells as well as in activated mouse astroglial cells, CXCL16 mRNA and protein is constitutively expressed and further up-regulated by tumour necrosis factor alpha (TNFalpha) and interferon-gamma (IFNgamma). CXCL16 is continuously released from glial cells by proteolytic cleavage which is rapidly enhanced by stimulation with phorbol-12-myristate-13-acetate (PMA). As shown by inhibitor studies, two distinct members of the disintegrin-like metalloproteinase family ADAM10 and 17 are involved in the constitutive and PMA-induced shedding of glial CXCL16. In addition to the chemokine, its receptor CXCR6 could be detected by quantitative RT-PCR in human glioma tissue, cultivated murine astrocytes and at a lower level in microglial cells. Functionally, recombinant soluble CXCL16 enhanced proliferation of CXCR6-positive murine astroglial and microglial cells. Thus, the transmembrane chemokine CXCL16 is expressed in the brain by malignant and inflamed astroglial cells, shed to a soluble form and targets not only activated T cells but also glial cells themselves.