Fractalkine在肾脏疾病中的作用

趋化因子是迄今为止发现最具多样性和最庞大的细胞因子亚家族，它可分为CXC亚族（α亚族）、CC亚族（β亚族）、C亚族（γ亚族）及CX3C亚族（δ亚族）。Fractalkine（FKN）是Bazan等在1997年经Blast分析法从美国国家生物技术信息中心的表达序列标签库中得到的趋化因子，是目前发现的CX3C亚族的唯一成员。     

CXC趋化因子在膀胱癌中的研究进展

膀胱癌（BCa）起源于尿路细胞（移形细胞）上皮，是泌尿系统中最常见的恶性肿瘤之一，其发病率和病死率在我国呈逐年升高的趋势。近年随着对膀胱癌生物学行为和患者诊疗方面的深入研究发现，单核细胞、巨噬细胞、内皮细胞等组织细胞和肿瘤细胞自身分泌产生的各种CXC趋化因子及其相互作用，在影响肿瘤细胞增殖、存活和诱导血管形成进而促进肿瘤发展、转移等方面发挥重要作用。本文旨在综述与膀胱癌发生发展、侵袭、转移相关的CXC趋化因子及其受体。     

在重症急性胰腺炎趋化因子生长相关α原癌基因蛋白和上皮中性粒细胞-活化蛋白78值是升高的

在急性胰腺炎的发病机制中 ,白介素是熟知的参与细胞因子 ,但在白细胞激活的趋化过程中 ,还涉及一族 8～ 12 kd的诱生型细胞因子。它们可分成 CXC和CC两个亚族 ,在前者 4个半胱氨酸残基的头 2个由另一个氨基酸所分开 ,而在后者头 2个半胱氨酸残基是相邻的。 CXC趋化因子又可分成两组 ,一组是在第 1个半胱氨酸残基前面的 N末端仍保留了谷氨酸 -亮氨酸 -精氨精序列 (EL R) ,而另一组是无此基序 ,这些不同的结构决定了趋化因子的生物学活性。EL R基序包括生长相关 α原癌基因蛋白 (GRO)、上皮中性粒细胞活化蛋白 (ENA) 78和白介素 8,…     

趋化因子及其受体在胃癌中的研究进展

目的了解趋化因子及其受体在胃癌的发生、发展及转移过程中的作用,为胃癌的诊断、治疗提供更好的途径。方法对有关趋化因子及其受体与胃癌关系研究的文献进行综述。结果目前已发现近50种趋化因子,与胃癌有关的研究较多者主要有CXC、CC及CX3C型趋化因子及其相应的受体,其在胃癌细胞的生长、增殖、侵袭及转移过程中具有促进作用,部分趋化因子还可诱导肿瘤耐药及辅助判断患者预后,其可通过m TOR、JAK2-STAT3通路等多种方式发挥作用。结论趋化因子及其受体在胃癌的发生、发展中扮演重要角色,对趋化因子及其受体的深入研究不仅可辅助胃癌的早期诊断、判断临床预后,更可为胃癌提供干预靶点。     

NSCLC组织SDF-1α/CXCR7通路蛋白表达及其与术后复发的关系

目的 检测非小细胞肺癌(non-small cell lung cancer,NSCLC)组织间质细胞衍生因子-1α(stromal derived factor 1α,SDF-1α)/趋化因子CXC受体7(chemokine CXC receptor 7,CXCR7)通路蛋白表达,并分析其与术后复发的关系. 方法 选...     

趋化因子在树突状细胞肿瘤疫苗研究中的进展

趋化因子是一类调节免疫细胞定向迁移的细胞因子,其与表达于细胞表面的趋化因子受体结合而发挥生物学功能.树突状细胞(DC)是重要的专职抗原递呈细胞,其主要的应用是制备成各种肿瘤疫苗,树突状细胞功能的行使与趋化因子及其受体介导的细胞迁移密切相关,趋化因子在树突状细胞游走与迁徙过程中始终发挥着调节、促进或抑制的作用,从而促使树突状细胞递呈抗原、激活初始T细胞,引起机体免疫反应,杀伤、消灭肿瘤细胞和炎性分子.     

CXC型趋化因子配体11在胆囊癌组织的表达及其对胆囊癌细胞增殖和侵袭的影响

目的:探讨CXC型趋化因子配体11(CXCL11)在胆囊癌组织中的表达水平及其对胆囊癌细胞增殖和侵袭的影响。方法:收集2017年1月至2020年12月宁波大学附属李惠利医院手术切除的47例胆囊癌患者肿瘤组织和癌旁组织进行免疫组化染色,并分析CXCL11蛋白表达与患者临床病理特征的相关性。其中女性26例,男性21例,年龄...     

单核细胞源性树突状细胞表达淋巴细胞趋化因子mRNA的初步研究

淋巴细胞趋化因子（Lptn）是趋化因子C族的惟一成员，具有趋化CD4^＋、CD8^＋T细胞和NK细胞的生物学特性，在肿瘤免疫治疗中具有重要意义。单核源性树突状细胞（DCs）分化过程中具有未成熟和成熟2个阶段，DCs具有不同的生物学特性与功能。我们采用体外实验研究了诱导培养的DCs（Mo-DCs）不同时期Lptn mRNA的表达情况。     

SDF-1/CXCR4调控Tip内皮细胞成血管效应的研究进展

基质细胞衍生因子－1 (stromal cell derived factor,SDF-1)是新近发现的一种趋化因子,SDF-1和趋化因子受体4 (CXC chemokine receptor 4,CXCR4)共同构成了特异性的SDF-1/CXCR4.血管内皮尖端细胞(endothelial tip cell)在新生血管的数量、分支及导向中发挥着重要作用.研究表明,SDF- 1/CXCR4轴对tip内皮细胞的行为和促血管形成起一定作用.本文就SDF- 1/CXCR4轴与Tip内皮细胞的关系及其促血管生成的机制做一综述.     

趋化因子CXCL14在不同转移潜能结直肠癌细胞中的表达及其与血管生成的关系

背景与目的:CXC趋化因子配体14(CXCL14)是一种与肿瘤细胞迁移密切相关的趋化因子,与多种恶性肿瘤的发生、进展有关.本研究旨在探讨CXCL14在结直肠癌细胞中的表达以及对血管生成的影响.方法:用RT-PCR与Western blot法分别检测CXCL14基因与蛋白在不同结直肠癌细胞株(HT-29、WiDr、CaC...     

Fimbrial lectins influence the chemokine repertoire in the urinary tract mucosa

The defense against mucosal infections relies on chemokines that recruit inflammatory cells to the mucosa. This study examined if the chemokine response to uro-pathogenic Escherichia coli is influenced by fimbrial expression. The CXC (CXCL1, CXCL5, CXCL8, CXCL9, CXCL10) and CC chemokines (CCL2, CCL3, CCL5) were quantified after in vitro infection of uro-epithelial cells with a fimbriated E. coli pyelonephritis isolate, or with P or type 1 fimbriated transformants of an avirulent E. coli K-12 strain. The response profile was shown to vary with the fimbrial type. Type 1 fimbriated E. coli elicited mainly CXCL1 and CXCL8, whereas P fimbriated E. coli stimulated CCL2 and CCL5 and class II were more potent chemokine inducers than class III P fimbriae. Chemokines were also quantified in urine samples from 73 patients with febrile urinary tract infection, and analyzed as a function of disease severity and fimbrial expression by the strain infecting each patient. A complex CXC and CC chemokine response was detected in patient urine, with a significant influence of the fimbrial type. The results show that virulence factors like fimbriae may modify the mucosal chemokine response. This mechanism may allow the host to adjust the inflammatory cell infiltrate to fit the infecting strain.     

Macrophage Inflammatory Protein-2 Promotes Angiogenesis, Cell Migration, and Tumor Growth in Hepatic Metastasis

Background In a mouse model of hepatic metastasis, we herein analyzed whether the CXC chemokine macrophage inflammatory protein (MIP)-2, a functional analogue of the human interleukin 8, stimulates tumor cell migration in vitro and angiogenesis and tumor growth in vivo. Methods By using chemotaxis chambers, CT26.WT colorectal tumor cell adhesion and migration were studied under stimulation with different concentrations of MIP-2. To evaluate angiogenesis and tumor growth in vivo, 1 × 10⁵ CT26.WT cells were implanted into the left liver lobe of syngeneic BALB/c mice, and 10, 100, and 1000 nM of MIP-2 or phosphate-buffered saline (controls) was injected into the peritumoral area. After 7 days, angiogenesis, proliferation, tumor growth, apoptosis, cleaved caspase 3, and CXCR-2 expression were analyzed by using intravital fluorescence microscopy, histology, immunohistochemistry, and fluorescence-activated cell sorting. Results In vitro, 98.8% of unstimulated CT26.WT cells showed CXCR-2 receptor expression. In the chemotaxis assays, MIP-2 provoked a dose-dependent increase of cell migration and a most pronounced cell adhesion at a dose of 100 nM. In vivo, MIP-2, in particular in a dose of 100 or 1000 nM, induced a significant increase of tumor capillary density and a marked widening of the angiogenic front at the tumor margin. Capillaries of the angiogenic front, but not of the tumor center, showed significant dilation, thus indicating a pronounced action of vascular endothelial growth factor. Tumor volume was significantly increased, in particular after 100 nM of MIP-2 stimulation, when compared with phosphate-buffered saline–treated controls, whereas only 1000 nM of MIP-2–treated animals additionally showed a higher frequency of apoptotic cell death within the tumor margin. Conclusions Our study indicates for the first time that the CXC chemokine MIP-2 promotes angiogenesis and growth of colorectal CT26.WT hepatic metastasis.     

Measurement of urinary chemokine and growth factor messenger RNAs: a noninvasive monitoring in lupus nephritis

Noninvasive molecular tests of urine cells have been developed to monitor the activity of kidney diseases. We evaluate whether measurement of urinary messenger RNA (mRNA) levels of chemokine and growth factor genes could distinguish between diffuse proliferative lupus nephritis (class IV LN) and others and whether it is able to predict the response to therapy. Prebiopsy urine samples were collected from 26 LN patients. Urine specimens were serially collected over a period of 6 months from class IV LN patients who were receiving standard immunosuppressive treatments. Urinary interferon-producing protein 10 and its CXC chemokine receptor (CXCR)3, transforming growth factor-beta (TGF-beta), and vascular endothelial growth factor (VEGF) mRNA levels were analyzed by quantitative real-time polymerase chain reactions. Levels of chemokine or growth factor mRNAs in urine could distinguish class IV LN from others, with a sensitivity of 85% and a specificity of 94%. The receiver-operative characteristic curve demonstrated that urine mRNA levels of these genes could identify active class IV LN with an accuracy greater than the current available clinical markers, namely systemic lupus erythematosus (SLE) disease activity index, proteinuria, renal function, or urinalysis. A significant reduction of interferon-producing protein 10 (IP-10), CXCR3, TGF-beta, and VEGF mRNA levels from baselines was observed in patients who responded to therapy, whereas the levels tended to increase in those who resisted to treatment. Measurement of urinary chemokine and growth factor mRNAs can precisely distinguish class IV LN from others. Temporal association between these markers and therapeutic response is demonstrated. This noninvasive approach serves as a practical tool in diagnosis and management of LN.     

Chemokine response to febrile urinary tract infection

BACKGROUND: Mucosal CXC chemokines recruit inflammatory cells to the infected urinary tract. The chemokine response repertoire of the urinary tract and the relationship to disease severity have not been examined, however. METHODS: This study quantified CXC (CXCL1, CXCL3, CXCL5, CXCL8, CXCL9, and CXCL10) and CC (CCL2, CCL4, and CCL5) chemokines in sequential urine samples obtained from 50 patients with febrile urinary tract infections during 24 hours after diagnosis. RESULTS: All patients had elevated chemokine levels, but bacteremic infections caused higher CXCL1, CXCL3, CXCL5, CXCL8, and CCL2 responses. CCL2 and CXCL8 levels were higher in patients with acute pyelonephritis symptoms and CCL2, CXCL3, CCL4, CXCL5, and CXCL10 were significantly correlated to C-reactive protein (CRP) and temperature. Women and men showed different chemokine responses. CONCLUSION: Febrile urinary tract infections are accompanied by a complex chemokine response. The response magnitude reflects disease severity, and the repertoire is influenced by gender and underlying disease.     

A novel small-molecule compound targeting CCR5 and CXCR3 prevents acute and chronic allograft rejection

BACKGROUND: Chemokines and chemokine receptors are critical in leukocyte recruitment, activation, and differentiation. Among them, CC chemokine receptor 5 (CCR5) and CXC chemokine receptor 3 (CXCR3) have been reported to play important roles in alloimmune responses and may be potential targets for posttransplant immunosuppression. METHODS: Fully major histocompatibility complex (MHC)-mismatched murine cardiac and islet transplant models were used to test the effect in vivo of a novel, small-molecule compound TAK-779 by targeting CCR5 and CXCR3 in acute allograft rejection. An MHC class II mismatched cardiac transplant model was used to evaluate its efficacy in chronic allograft rejection. Intragraft expression of cytokines, chemokines, and chemokine receptors was measured by quantitative real-time polymerase chain reaction and by histological analysis. RESULTS: Treatment of TAK-779 significantly prolonged allograft survival across the MHC barrier in two distinct transplant models. The treatment downregulated local immune activation as observed by the reduced expression of several chemokines, cytokines, and chemokine receptors. Thereby, the recruitment of CD4, CD8, and CD11c cells into transplanted allografts were inhibited. Furthermore, TAK-779 treatment significantly attenuated the development of chronic vasculopathy, fibrosis, and cellular infiltration. CONCLUSIONS: Antagonism of CCR5 and CXCR3 has a substantial therapeutic effect on inhibiting both acute and chronic allograft rejection. CCR5 and CXCR3 are functional in the process of allograft rejection and may be potential targets in clinical transplantation in the future.     

In vivo luminescent imaging of cyclosporin A-mediated cancer progression in rats

BACKGROUND: Immunosuppressed individuals undergoing organ transplantation are at increased risk of recurrences of initial cancers, although how immunosuppressive therapy increases early cancer metastasis remains unclear. METHODS: The metastatic fate of luciferase-expressing rat metastatic colon cancer cells (luc-RCN-H4) injected intravenously into the liver of syngeneic and allogeneic rats was examined in the presence of the immunosuppressant cyclosporin A (CsA) by in vivo luminescent technique. With respect to potential tumor-progressing factors, contribution of chemokine receptors and transforming growth factor (TGF)-beta1 to early metastasis was evaluated using their specific signaling inhibitors. RESULTS: F344 rats injected in the liver with luc-RCN-H4 cells did not always exhibit the formation of tumors and showed a dormant state as long as 60 days after inoculation without CsA. However, CsA released early luc-RCN-H4 cells from dormancy within 2 weeks at nearly 100% in liver and preferentially promoted metastasis to the lymph nodes (approximately 40%). A similar dissemination occurred even in minor histocompatibility complex-disparate hosts. As a tumor-progressing factor, RCN-H4 cells aberrantly expressed chemokine receptors CXCR4 and CCR7. The chemokine receptor (CXC) R4-specific antagonist AMD3100 decreased early metastasis of luc-RCN-H4 cells in rats with ischemic liver conditions (P<0.05), but CsA treatment did not enhance early adhesion. Use of CsA was able to facilitate TGF-beta1 expression and the subsequent TGF-beta-mediated random migration was blocked by the use of the specific signaling inhibitor SB431542 in vitro. CONCLUSIONS: Whereas the chemokine receptor expression by cancer cells is implicated with early organotropic dissemination even under CsA-mediated immune suppression, rather, CsA enhances the late-phase progression after tumor adhesion through TGF-beta1 expression.     

Comparison between VDR analogs and current immunosuppressive drugs in relation to CXCL10 secretion by human renal tubular cells

During kidney allograft rejection, CXC chemokine ligand 10 (CXCL10)–CXC chemokine receptor 3 (CXCR3) trafficking between peripheral blood and tissues initiates alloresponse and perpetuates a self‐inflammatory loop; thus, CXCL10–CXCR3 axis could represent a pharmacologic target. In this perspective, immunosuppressors targeting graft‐resident cells, beside immune cells, could be very advantageous. Vitamin D receptor (VDR) agonists exhibit considerable immunomodulatory properties. This study aimed to investigate whether elocalcitol and BXL‐01‐0029 could decrease the expression of CXCL10 in activated renal tubular cells in vitro and thus be useful in kidney allograft rejection treatment. Experiments were performed in human tubular renal cells stimulated with interferon‐γ + tumor necrosis factor‐α with and without VDR agonists, tacrolimus, sirolimus, hydrocortisone, methylprednisolone, cyclosporin A and mycophenolate mofetil. CXCL10 protein secretion and gene expression were measured by ELISA and by quantitative PCR. Specific inhibitors were used to investigate intracellular pathways involved in tubular cells activation. For IC₅₀ determination and comparison, dose‐response curves with VDR agonists, tacrolimus and mycophenolic acid were performed. Elocalcitol and BXL‐01‐0029 inhibited CXCL10 secretion by renal cells, without affecting cell viability, while almost all the immunosuppressors were found to be ineffective, except for tacrolimus and mycophenolate mofetil. BXL‐01‐0029 was the most potent drug and, notably, it was found to be capable of allowing reduction in tacrolimus‐inhibitory doses. Our data suggest that BXL‐01‐0029 could potentially be a dose‐reducing agent for conventional immunosuppressors in kidney rejection management.     

Cytomegalovirus accelerates chronic allograft nephropathy in a rat renal transplant model with associated provocative chemokine profiles

BACKGROUND: Studies have shown that rat cytomegalovirus (RCMV) infection accelerates transplant vascular sclerosis (TVS) in rat heart and small bowel allotransplants. In these models, RCMV-accelerated TVS results from increased graft infiltration of inflammatory cells through up-regulation of chemokine expression. The aim of this study was to determine if RCMV infection accelerates renal transplant chronic allograft nephropathy (CAN), and the role of chemokines in this process. METHODS: F344 kidneys were transplanted into Lewis recipients with and without RCMV infection. To monitor CAN, serum creatinine (Cr) levels were measured starting at 4 weeks posttransplantation. At 7 and 21 days, and at terminal rejection, grafts were examined for histologic changes, inflammatory cell infiltrates, viral load, and chemokine expression profiles. RESULTS: By week 8, serum Cr showed significant elevation (P < .01) in the RCMV-infected group vs uninfected group, and remained significantly elevated through the end of the study. RCMV+ renal allografts had significant inflammatory cell infiltration and increased CAN at postoperative day (POD) 28. The CC chemokines RANTES, MCP-1, and MIP-1alpha, and the CXC chemokine IP-10 were up-regulated in RCMV-infected vs uninfected allografts. IP-10 was significantly up-regulated early in the process, whereas RANTES and MCP-1 were induced at a later time. CONCLUSIONS: RCMV infection accelerates CAN, with associated graft inflammatory infiltrates, which is paralleled by an increase in expression of CC and CXC chemokines. Our findings suggest that the early induction of IP-10 in the infected allografts promotes alterations in T-cell and monocyte migration to the graft, which initiates accelerated inflammatory and fibrotic changes associated with CAN.     

Contribution of CXCL16/CXCR6 pathway activated by inflammation to atherosclerosis in patients with end-stage renal disease

Objective To investigate the effects of CXC chemokine ligand 16 (CXCL16)/CXC chemokine receptor 6 (CXCR6) pathway on cholesterol accumulation of atherosclerosis in the radial artery of end-stage renal disease (ESRD) patients under inflammatory stress and further investigate its potential mechanisms modulated by purinergic receptor P2X ligand-gated ion channel 7 (P2X7R). Methods According to plasma C-reactive protein (CRP), forty ESRD patients were divided into control group (CRP＜3.0 mg/L, n=15) and inflammation group (CRP≥3.0 mg/L, n=25). Biochemical index and lipid spectrum of patients were measured. Tissues from the radial artery of patients receiving arteriovenostomy were removed surgically. Foam cell formation was observed by hematoxylin-eosin (HE) and cholesterol accumulation was assessed by filipin staining. CXCL16/CXCR6 pathway related protein expression, P2X7R protein expression and the expression of monocyte chemotactic protein 1 (MCP-1), tumor necrosis factor α (TNF-α) and CD68 were detected by immunohistochemistry staining and immunofluorescence staining. Results Compared with that in control group, protein expression of MCP-1 and TNF-α in radial arteries were increased in inflammation group accompanied with macrophage infiltration (P＜0.05). Further more, there was significantly increased foam cell formation in continuous cross-sections of radial arteries in inflammation group, which was closely correlated with increased protein expression of CXCL16, CXCR6 and a disintegrin and metalloproteinase (ADAM)-10 (P＜0.05). CXCL16 expression was positively correlated with CRP level (r=0.79, P＜0.05) and P2X7R expression (r=0.65, P＜0.05). Conclusion Inflammation contributes to foam cell formation in the radial artery of ESRD patients by activating the CXCL16/CXCR6 pathway, and promotes atherosclerosis, which is possibly regulated by P2X7R activation.     

Plasma Cytokines and Chemokines in Primary Graft Dysfunction Post-Lung Transplantation

Primary graft dysfunction (PGD) after lung transplantation causes significant morbidity and mortality. We aimed to determine the role of cytokines and chemokines in PGD. This is a multicenter case–control study of PGD in humans. A Luminex analysis was performed to determine plasma levels of 25 chemokines and cytokines before and at 6, 24, 48 and 72 h following allograft reperfusion in 25 cases (grade 3 PGD) and 25 controls (grade 0 PGD). Biomarker profiles were evaluated using a multivariable logistic regression and generalized estimating equations. PGD cases had higher levels of monocyte chemotactic protein-1 (MCP-1)/chemokine CC motif ligand 2 (CCL2) and interferon (IFN)-inducible protein (IP-10)/chemokine CXC motif ligand 10 (CXCL10) (both p < 0.05), suggesting recruitment of monocytes and effector T cells in PGD. In addition, PGD cases had lower levels of interleukin (IL-13) (p = 0.05) and higher levels of IL-2R (p = 0.05). Proinflammatory cytokines, including tumor necrosis factor (TNF)-α, and IFN-γ decreased to very low levels after transplant in both PGD cases and controls, exhibiting no differences between the two groups. These findings were independent of clinical variables including diagnosis in multivariable analyses, but may be affected by cardiopulmonary bypass. Profound injury in clinical PGD is distinguished by the upregulation of selected chemokine pathways, which may useful for the prediction or early detection of PGD if confirmed in future studies.