BACKGROUND & AIMS: :Opsoclonus-myoclonus syndrome (OMS) is a neuroinflammatory disorder associated with remote cancer. To understand more clearly the role of inflammatory mediators, the concentration of CXCR3 ligands CXCL10, CXCL9 and CXCL11 was measured in 245 children with OMS and 81 paediatric controls using enzyme-linked immunosorbent assay (ELISA), and CXCR3 expression on CD4(+) T cells was measured by flow cytometry. Mean cerebrospinal fluid (CSF) CXCL10 was 2·7-fold higher in untreated OMS than controls. Intrathecal production was demonstrated by significantly different CXCL10 CSF : serum ratios. The dichotomized 'high' CSF CXCL10 group had higher CSF leucocyte count (P = 0·0007) and B cell activating factor (BAFF) and CXCL13 concentrations (P < 0·0001). CSF CXCL10 did not correlate with clinical severity or relapse using grouped data, although it did in some patients. Among seven types of immunotherapy, including rituximab or chemotherapy, only adrenocorticotrophic hormone (ACTH) monotherapy showed reduced CSF CXCL10, but prospective longitudinal studies of ACTH combination therapies indicated no reduction in CXCL10 despite clinical improvement (P < 0·0001). CXCL10 concentrations were 11-fold higher in CSF and twofold higher in serum by multiplexed fluorescent bead-based immunoassay than enzyme-linked immunosorbent assay, but the two correlated (r = 0·7 and 0·83). In serum, no group differences for CXCL9 or CXCL11 were found. CXCR3 expression on CD4(+) T cells was fivefold higher in those from CSF than blood, but was not increased in OMS or altered by conventional immunotherapy. These data suggest alternative roles for CXCL10 in OMS. Over-expression of CXCL10 was not reduced by clinical immunotherapies as a whole, indicating the need for better therapeutic approaches.

背景与目标： : 肌阵挛综合征 (OMS) 是一种与远端癌症相关的神经炎症性疾病。为了更清楚地了解炎症介质的作用，使用酶联免疫吸附试验 (ELISA) 在245例OMS儿童和81例儿科对照中测量了CXCR3配体CXCL10，CXCL9和CXCL11的浓度，并通过流式细胞术测量了CXCR3在CD4 () T细胞上的表达。未经治疗的OMS的平均脑脊液 (CSF) CXCL10比对照组高2·7倍。鞘内产生的CXCL10 csf  :  血清比率明显不同。分离的 “高” CSF CXCL10组具有较高的CSF白细胞计数 (p   =   0·0007) 和b细胞活化因子 (BAFF) 和CXCL13浓度 (p  <  0·0001)。使用分组数据，CSF CXCL10与临床严重程度或复发无关，尽管在某些患者中确实如此。在包括利妥昔单抗或化疗在内的7种免疫治疗中，只有促肾上腺皮质激素 (ACTH) 单药治疗显示CSF CXCL10降低，但ACTH联合治疗的前瞻性纵向研究表明，尽管临床有所改善，但CXCL10并未降低 (p  <  0·0001)。基于多重荧光珠的免疫测定在脑脊液中CXCL10的浓度比酶联免疫吸附测定高11倍，血清中CXCL10的浓度高2倍，但两者相关 (r   =   0·7和0·83)。在血清中，未发现CXCL9或CXCL11的组差异。CSF中CD4 () T细胞上的CXCR3表达比血液高五倍，但在OMS中并未增加或通过常规免疫疗法改变。这些数据表明CXCL10在OMS中的替代作用。整个临床免疫疗法并未降低CXCL10的过表达，这表明需要更好的治疗方法。

BACKGROUND & AIMS: :Lung transplantation remains the only effective therapy for patients with end-stage lung disease, but survival is limited by the development of obliterative bronchiolitis (OB). The chemokine receptor CXCR3 and two of its ligands, CXCL9 and CXCL10, have been identified as important mediators of OB. However, the relative contribution of CXCL9 and CXCL10 to the development of OB and the mechanism of regulation of these chemokines has not been well defined. In this study, we demonstrate that CXCL9 and CXCL10 are up-regulated in unique patterns following tracheal transplantation in mice. In these experiments, CXCL9 expression peaked 7 days posttransplant, while CXCL10 expression peaked at 1 day and then again 7 days posttransplant. Expression of CXCL10 was also up-regulated in a novel murine model of lung ischemia, and in bronchoalveolar lavage fluid taken from human lungs 24 h after lung transplantation. In further analysis, we found that 3 h after transplantation CXCL10 is donor tissue derived and not dependent on IFN-gamma or STAT1, while 24 h after transplantation CXCL10 is from recipient tissue and regulated by IFN-gamma and STAT1. Expression of both CXCL9 and CXCL10 7 days posttransplant is regulated by IFN-gamma and STAT1. Finally, we demonstrate that deletion of CXCR3 in recipients reduces airway obliteration. However, deletion of either CXCL9 or CXCL10 did not affect airway obliteration. These data show that in this murine model of obliterative bronchiolitis, these chemokines are differentially regulated following transplantation, and that deletion of either chemokine alone does not affect the development of airway obliteration.

背景与目标： : 肺移植仍然是终末期肺部疾病患者的唯一有效疗法，但生存受到闭塞性细支气管炎 (OB) 的发展的限制。趋化因子受体CXCR3及其两个配体CXCL9和CXCL10已被确定为OB的重要介质。然而，CXCL9和CXCL10对OB的发展以及这些趋化因子的调控机制的相对贡献尚未明确。在这项研究中，我们证明了CXCL9和CXCL10在小鼠气管移植后以独特的方式上调。在这些实验中，CXCL9表达在移植后7天达到峰值，而CXCL10表达在移植后1天达到峰值，然后在移植后7天再次达到峰值。在新型的小鼠肺缺血模型和肺移植后24小时从人肺中提取的支气管肺泡灌洗液中，CXCL10的表达也被上调。在进一步的分析中，我们发现移植后3小时CXCL10是来源的供体组织，不依赖于IFN-γ 或STAT1，而移植后24小时CXCL10来自受体组织，并受IFN-γ 和STAT1调节。移植后7天CXCL9和CXCL10的表达受IFN-γ 和stat1调节。最后，我们证明受体中CXCR3的缺失减少了气道闭塞。然而，CXCL9或CXCL10的缺失并不影响气道闭塞。这些数据表明，在这种闭塞性细支气管炎的鼠模型中，这些趋化因子在移植后受到差异调节，并且单独删除任何一种趋化因子都不会影响气道闭塞的发展。

BACKGROUND & AIMS: :Type 1 diabetes (T1D) is due to antigen-specific assaults on the insulin producing pancreatic β-cells by diabetogenic T-helper (Th)1 cells. (C-X-C motif) ligand (CXCL)10, an interferon-γ inducible Th1 chemokine, and its receptor, (C-X-C motif) receptor (CXCR)3, have an important role in different autoimmune diseases. High circulating CXCL10 levels were detected in new onset T1D patients, in association with a Th1 autoimmune response. Furthermore β-cells produce CXCL10, under the influence of Th1 cytokines, that suppresses their proliferation. Viral β-cells infections induce cytokines and CXCL10 expression, inducing insulin-producing cell failure in T1D. CXCL10/CXCR3 system plays a critical role in the autoimmune process and in β-cells destruction in T1D. Blocking CXCL10 in new onset diabetes seems a possible approach for T1D treatment.

背景与目标： : 1型糖尿病 (T1D) 是由于产生糖尿病的T辅助 (Th)1细胞对产生胰岛素的胰岛 β 细胞的抗原特异性攻击所致。(C-x-c motif) 配体 (CXCL)10是一种 γ 干扰素诱导的Th1趋化因子，其受体 (c-x-c motif) 受体 (CXCR)3在不同的自身免疫性疾病中具有重要作用。在新发T1D患者中检测到高循环CXCL10水平，并伴有Th1自身免疫反应。此外，β 细胞在Th1细胞因子的影响下产生CXCL10，从而抑制其增殖。病毒 β 细胞感染诱导细胞因子和CXCL10表达，诱导T1D产生胰岛素的细胞衰竭。CXCL10/CXCR3系统在T1D的自身免疫过程和 β 细胞破坏中起关键作用。在新发糖尿病中阻断CXCL10似乎是T1D治疗的可能方法。

BACKGROUND & AIMS: BACKGROUND:Recent studies have identified T cells and natural killer T (NKT) cells as important mediators in renal ischemia-reperfusion (I/R) injury. The recruitment of these cells is induced by chemotaxis factors. We investigated the effects of blocking CXCR3 and CCR5 by an antagonist (TAK) using a rat renal I/R injury model. METHODS:The Sprague-Dawley rats were either subjected to sham operation or left renal occlusion for 45 min followed by reperfusion and contralateral nephrectomy. The control or TAK groups were, respectively, injected phosphate-buffered saline or TAK at 30 min prior to clamp. Serum creatinine, tubular injury, chemokines expression and infiltrating cells were assessed. RESULTS:TAK treatment significantly suppressed the elevation in serum creatinine (sham 0.40 ± 0.05 mg/dL, control 2.86 ± 0.67 mg/dL, TAK 1.60 ± 0.73 mg/dL) and resulted in a lower tubular injury score compared with the control group (sham 0, control 4.8 ± 0.3, TAK 3.3 ± 1). The mRNA expression of chemokines that bind to CXCR3 and CCR5 in the post-ischemic kidneys was elevated at 1 h after reperfusion in each group. Moreover, the infiltration of CD4+ T cells and CD8+ NKT cells in the control group increased compared with the sham group and TAK injection significantly suppressed the number of CD4+ T cells (sham 13.5 ± 3.5 × 10(4) cells, control 28.9 ± 15.4 × 10(4) cells, TAK 11.8 ± 3.5 × 10(4) cells) and the number of CD8+ NKT cells (sham 11.7 ± 5.4 × 10(4) cells, control 30.1 ± 8.6 × 10(4) cells, TAK 11.8 ± 2.9 × 10(4) cells). CONCLUSIONS:These findings suggest that the blocking of CXCR3 and CCR5 suppress the infiltration of T cells and NKT cells and have a protective effect on kidneys that are injured by I/R.

背景与目标：

BACKGROUND & AIMS: :The chemokine receptor CXCR3 is expressed on the surface of both resting and activated T lymphocytes. We describe in this study the endocytosis of CXCR3 using T lymphocytes and CXCR3 transfectants. Chemokine-induced CXCR3 down-regulation occurred in a rapid, dose-dependent manner, with CXCL11 the most potent and efficacious ligand. Endocytosis was mediated in part by arrestins, but appeared to occur independently of clathrin and caveolae. In contrast to other chemokine receptors, which are largely recycled to the cell surface within an hour, cell surface replenishment of CXCR3 occurred over several hours and was dependent upon mRNA transcription, de novo protein synthesis, and transport through the endoplasmic reticulum and Golgi. Confocal microscopy and Western blotting confirmed the fate of endocytosed CXCR3 to be degradation, mediated in part by lysosomes and proteosomes. Site-directed mutagenesis of the CXCR3 C terminus revealed that internalization and degradation were independent of phosphorylation, ubiquitination, or a conserved LL motif. CXCR3 was found to be efficiently internalized in the absence of ligand, a process involving a YXXL motif at the extreme of the C terminus. Although freshly isolated T lymphocytes expressed moderate cell surface levels of CXCR3, they were only responsive to CXCL11 with CXCL9 and CXCL10 only having significant activity on activated T lymphocytes. Thus, the activities of CXCR3 are tightly controlled following mRNA translation. Because CXCR3(+) cells are themselves a source of IFN-gamma, which potently induces the expression of CXCR3 ligands, such tight regulation of CXCR3 may serve as a control to avoid the unnecessary amplification of activated T lymphocyte recruitment.

背景与目标： : 趋化因子受体CXCR3在静止和活化的T淋巴细胞表面均表达。在这项研究中，我们使用T淋巴细胞和CXCR3转染子描述了CXCR3的内吞作用。趋化因子诱导的CXCR3下调以快速，剂量依赖性方式发生，其中CXCL11是最有效的配体。内吞作用部分由抑制素介导，但似乎独立于网格蛋白和小凹而发生。与其他趋化因子受体 (在一小时内大量回收到细胞表面) 相反，CXCR3的细胞表面补充发生了几个小时，并且取决于mRNA转录，从头蛋白质合成以及通过内质网和高尔基体的转运。共聚焦显微镜和Western印迹证实了内吞CXCR3降解的命运，部分由溶酶体和蛋白质体介导。CXCR3 C末端的定点诱变表明，内化和降解与磷酸化，泛素化或保守的LL基序无关。发现CXCR3在没有配体的情况下有效内化，该过程涉及C末端的YXXL基序。尽管新鲜分离的T淋巴细胞表达中等水平的CXCR3细胞表面，但它们仅对CXCL11有反应，而CXCL9和CXCL10仅对活化的T淋巴细胞具有显着活性。因此，CXCR3的活性在mRNA翻译后受到严格控制。由于CXCR3 () 细胞本身是IFN-γ 的来源，可以有效地诱导CXCR3配体的表达，因此对CXCR3的这种严格调节可以作为一种控制，以避免不必要的活化T淋巴细胞募集的扩增。

BACKGROUND & AIMS: :CCR9 + T helper (Th) cells can induce Sjögren-like symptoms in mice and both CCR9 + Th cells and their ligand CCL25 are increased in the salivary glands of primary Sjögren's syndrome (pSS) patients. Increased circulating CCR9 + Th cells are present in pSS patients. CCR9 + Th cells are hyperresponsive to IL-7, secrete high levels of IFN-γ, IL-21, IL-17 and IL-4 and potently stimulate B cells in both patients and healthy individuals. Our aim was to study co-expression of chemokine receptors on CCR9 + Th cells and whether in pSS this might differentially affect CCR9 + Th cell frequencies. Frequencies of circulating CCR9 + and CCR9- Th cells co-expressing CXCR3, CCR4, CCR6 and CCR10 were studied in pSS patients and healthy controls. CCL25, CXCL10, CCL17, CCL20 and CCL27 mRNA and protein expression of salivary gland tissue of pSS and non-Sjögren's sicca (non-SS) patients was assessed. Chemotaxis assays were performed to study migration induced by CXCL10 and CCL25. Higher expression of CXCR3, CCR4 and CCR6 but not CCR10 was observed on CCR9 + Th cells as compared to cells lacking CCR9. Decreased frequencies of circulating memory CCR9 + CXCR3+ Th cells were found in pSS patients, which was most pronounced in the effector memory subset. Increased salivary gland CCL25 and CXCL10 expression significantly correlated and both ligands functioned synergistically based on in vitro induced chemotaxis. Decreased memory CXCR3 + CCR9+ Th cells in blood of pSS patients may be due to a concerted action of overexpressed ligands at the site of inflammation in the salivary glands facilitating their preferential migration and positioning in the lymphocytic infiltrates.

背景与目标： : CCR9 T辅助 (Th) 细胞可以在小鼠中诱导sj ö gren样症状，并且原发性sj ö gren综合征 (pSS) 患者的唾液腺中CCR9 Th细胞及其配体CCL25均增加。pSS患者存在循环CCR9 + Th细胞增加。CCR9 + Th细胞对IL-7反应过度，分泌高水平的IFN-γ，IL-21，IL-17和IL-4，并有效刺激患者和健康个体的b细胞。我们的目的是研究趋化因子受体在CCR9 Th细胞上的共表达，以及在pSS中这是否可能差异影响CCR9 Th细胞频率。在pSS患者和健康对照中研究了共同表达CXCR3，CCR4，CCR6和CCR10的循环CCR9和CCR9- Th细胞的频率。评估了pSS和非sj ö gren sicca (非SS) 患者唾液腺组织的CCL25，CXCL10，CCL17，CCL20和CCL27 mRNA和蛋白表达。进行趋化性测定以研究CXCL10和ccl25诱导的迁移。与缺乏CCR9的细胞相比，在CCR9 Th细胞上观察到CXCR3，CCR4和CCR6的表达更高，但没有CCR10。在pSS患者中发现循环记忆CCR9 CXCR3 Th细胞的频率降低，这在效应记忆子集中最为明显。唾液腺CCL25和CXCL10表达的增加显着相关，并且两个配体基于体外诱导的趋化性协同作用。pSS患者血液中记忆CXCR3 CCR9 Th细胞减少可能是由于唾液腺炎症部位过度表达的配体协同作用，促进了它们在淋巴细胞浸润中的优先迁移和定位。

BACKGROUND & AIMS: :Chemokines and their receptors are essential for leukocyte trafficking, and are also involved in cancer metastasis to specific organs. Although the migration of tumor cells into the lymph nodes is an important aspect of cancer, the processes involved are poorly understood. Chemokine receptors CCR7 and CXCR3 have been shown to play an important role in tumor cell migration and lymph node metastasis. Therefore, the assessment of chemokine receptor expression on lung adenocarcinomas may improve the prediction of the spread of this carcinoma to the lymph nodes. In this study, we examined the expression and function of these two chemokine receptors (CCR7 and CXCR3) in lung adenocarcinoma. By using flow cytometry, they were detected in all of the lung adenocarcinoma cell lines examined. In the chemotaxis assays, A549 cells exhibited CCL21-induced migration, which was significantly suppressed by neutralizing anti-CCR7 antibody. The CXCL10-induced migration of A549 cells was also significantly suppressed by neutralizing anti-CXCR3 antibody. In clinical lung adenocarcinoma samples, we found the expression of CCR7 and CXCR3 in 65 and 90% cases, respectively, most of which had lymph node metastasis. Importantly, the expression of CCR7 was significantly associated with lymph node metastasis, although the expression of CXCR3 was not. These results suggest that the activation of CCR7 and CXCR3 with their ligands preferentially stimulates lung adenocarcinoma metastasis to the draining lymph nodes.

背景与目标： : 趋化因子及其受体对于白细胞运输至关重要，并且还参与癌症向特定器官的转移。尽管肿瘤细胞向淋巴结的迁移是癌症的重要方面，但对所涉及的过程知之甚少。趋化因子受体CCR7和CXCR3已被证明在肿瘤细胞迁移和淋巴结转移中起重要作用。因此，评估趋化因子受体在肺腺癌上的表达可能会改善该癌向淋巴结扩散的预测。在这项研究中，我们检查了这两种趋化因子受体 (CCR7和CXCR3) 在肺腺癌中的表达和功能。通过使用流式细胞仪，在所有检查的肺腺癌细胞系中检测到它们。在趋化性测定中，A549细胞表现出CCL21-induced的迁移，其被中和anti-CCR7抗体显著抑制。A549细胞的CXCL10-induced迁移也被中和anti-CXCR3抗体显著抑制。在临床肺腺癌样本中，我们发现CCR7和CXCR3分别在65和90% 例中表达，其中大多数有淋巴结转移。重要的是，CCR7的表达与淋巴结转移显着相关，尽管CXCR3的表达并非如此。这些结果表明，CCR7和CXCR3及其配体的激活优先刺激肺腺癌转移至引流淋巴结。

BACKGROUND & AIMS: AIMS:The CXC chemokine CXCL10 is up-regulated in the infarcted myocardium and limits cardiac fibrosis by inhibiting growth factor-mediated fibroblast migration. CXCL10 signals by binding to its receptor CXCR3; however, recently CXCR3-independent CXCL10 actions have been suggested. Our study explores the role of CXCR3 signalling in myocardial infarction and investigates its involvement in mediating the anti-fibrotic effects of CXCL10. METHODS AND RESULTS:Wild-type and CXCR3 null mice underwent reperfused infarction protocols. CXCL10 was markedly induced in the infarct; in contrast, expression of the other two CXCR3 ligands, CXCL9 and CXCL11 was extremely low. CXCR3 loss did not affect scar size, geometric ventricular remodelling, collagen deposition, and systolic dysfunction of the infarcted heart. CXCR3 null mice had increased peak neutrophil recruitment and delayed myofibroblast infiltration in the infarcted heart, but exhibited comparable myocardial expression of pro-inflammatory cytokines and chemokines. In vitro, CXCL10 did not modulate Transforming Growth Factor (TGF)-β signalling, but inhibited basic fibroblast growth factor (bFGF)-induced cardiac fibroblast migration in both wild-type and CXCR3 null cells. Treatment of fibroblasts with heparinase and chondroitinase to cleave glycosaminoglycan chains abrogated the inhibitory effects of CXCL10 on cell migration. CONCLUSION:CXCR3 signalling does not critically regulate cardiac remodelling and dysfunction following myocardial infarction. The anti-fibrotic effects of CXCL10 in the healing infarct and in isolated cardiac fibroblasts are CXCR3-independent and may be mediated through proteoglycan signalling. Thus, administration of CXCR3-defective forms of CXCL10 may be an effective anti-fibrotic strategy in the remodelling myocardium without activating a potentially injurious, CXCR3-driven T cell response.

背景与目标：

BACKGROUND & AIMS: :The chemokine receptor CXCR3 promotes the trafficking of activated T and NK cells in response to three ligands, CXCL9, CXCL10, and CXCL11. Although these chemokines are produced in the CNS in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE), their role in the pathogenesis of CNS autoimmunity is unresolved. We examined the function of CXCR3 signaling in EAE using mice that were deficient for CXCR3 (CXCR3(-/-)). The time to onset and peak disease severity were similar for CXCR3(-/-) and wild-type (WT) animals; however, CXCR3(-/-) mice had more severe chronic disease with increased demyelination and axonal damage. The inflammatory lesions in WT mice consisted of well-demarcated perivascular mononuclear cell infiltrates, mainly in the spinal cord and cerebellum. In CXCR3(-/-) mice, these lesions were more widespread throughout the CNS and were diffused and poorly organized, with T cells and highly activated microglia/macrophages scattered throughout the white matter. Although the number of CD4(+) and CD8(+) T cells infiltrating the CNS were similar in CXCR3(-/-) and WT mice, Foxp3(+) regulatory T cells were significantly reduced in number and dispersed in CXCR3(-/-) mice. The expression of various chemokine and cytokine genes in the CNS was similar in CXCR3(-/-) and WT mice. The genes for the CXCR3 ligands were expressed predominantly in and/or immediately surrounding the mononuclear cell infiltrates. We conclude that in EAE, CXCR3 signaling constrains T cells to the perivascular space in the CNS and augments regulatory T cell recruitment and effector T cell interaction, thus limiting autoimmune-mediated tissue damage.

背景与目标： : 趋化因子受体CXCR3促进活化的T和NK细胞的运输，以响应三个配体CXCL9，CXCL10和cxcl11。尽管这些趋化因子是在多发性硬化症和实验性自身免疫性脑脊髓炎 (EAE) 的中枢神经系统中产生的，但它们在中枢神经系统自身免疫发病机理中的作用尚未解决。我们使用缺乏CXCR3(-/-)) 的小鼠检查了EAE中CXCR3信号传导的功能。CXCR3(-/-) 和野生型 (WT) 动物的发病时间和高峰疾病严重程度相似; 然而，CXCR3(-/-) 小鼠患有更严重的慢性疾病，脱髓鞘和轴突损伤增加。WT小鼠的炎性病变由边界明确的血管周围单核细胞浸润组成，主要在脊髓和小脑中。在CXCR3(-/-) 小鼠中，这些病变在整个中枢神经系统中更为广泛，并且弥散且组织不良，T细胞和高度活化的小胶质细胞/巨噬细胞散布在整个白质中。尽管在CXCR3(-/-) 和WT小鼠中浸润CNS的CD4 () 和CD8 () T细胞的数量相似，但在CXCR3(-/-) 小鼠中，Foxp3 () 调节性T细胞的数量显着减少并分散。在CXCR3(-/-) 和WT小鼠中，CNS中各种趋化因子和细胞因子基因的表达相似。CXCR3配体的基因主要在单核细胞浸润处和/或紧邻其周围表达。我们得出的结论是，在EAE中，CXCR3信号传导将T细胞约束到CNS中的血管周围空间，并增强调节性T细胞募集和效应T细胞相互作用，从而限制了自身免疫介导的组织损伤。

BACKGROUND & AIMS: :The CC chemokine known as 6Ckine (SLC, Exodus-2, or TCA4) has been identified as a ligand for CCR7. Mouse 6Ckine has also been shown to signal through mouse CXCR3 and share some of the activities of IFN-gamma inducible protein 10 and monokine induced by IFN-gamma. Nonetheless, human 6Ckine has not been shown to bind CXCR3 receptor or have angiostatic activity. In this study, we report that human 6Ckine does not induce a calcium flux in either human CXCR3 or mouse CXCR3 transfected cells, although it is an equally potent agonist as mouse 6Ckine and human macrophage inflammatory protein-3beta in human CCR7 transfected cells. Mouse 6Ckine (but not human 6Ckine) is capable of competing with radiolabeled IFN-gamma inducible protein 10 for human CXCR3. In addition, radiolabeled human 6Ckine does not bind to either human CXCR3 or mouse CXCR3. Together these data suggest that human CC chemokine 6Ckine is not a ligand for the human or mouse CXC chemokine receptor CXCR3.

背景与目标： : 被称为6ckine的CC趋化因子 (SLC，Exodus-2或TCA4) 已被确定为ccr7的配体。小鼠6Ckine也已显示通过小鼠CXCR3发出信号，并共享IFN-γ 诱导蛋白10和IFN-γ 诱导的单核因子的一些活性。尽管如此，尚未显示人6ckine结合CXCR3受体或具有血管抑制活性。在这项研究中，我们报告了人6ckine不会在人CXCR3或小鼠CXCR3转染的细胞中诱导钙通量，尽管它是与人CCR7转染的细胞中的小鼠6ckine和人巨噬细胞炎性protein-3beta同样有效的激动剂。小鼠6Ckine (但不是人6Ckine) 能够与放射性标记的IFN-γ 诱导蛋白10竞争人cxcr3。此外，放射性标记的人6ckine不与人CXCR3或小鼠CXCR3结合。这些数据一起表明，人CC趋化因子6ckine不是人或小鼠CXC趋化因子受体cxcr3的配体。

BACKGROUND & AIMS: BACKGROUND:Since human peripheral eosinophils have been shown to migrate to the CXC chemokine receptor 3 (CXCR3) ligands IFN-gamma-inducible protein 10 (IP10) and monokine induced by IFN-gamma (Mig), this confirms that CXCR3 is functionally expressed on these cells. IP10 expression has been shown to be increased in the airways of asthmatics. Eosinophil accumulations are found in bronchoalveolar lavage fluid (BALF) from patients with chronic eosinophilic pneumonia (CEP). To examine the contribution of IP10 and Mig in the pathogenesis of CEP, we measured the concentration of IP10 and Mig, and evaluated the expression of CXCR3 on eosinophils in BALF taken from patients with CEP. METHODS:The concentrations of IP10 and Mig in BALF were measured by ELISA. The proportion of CXCR3-expressing CD4+ T cells and CD16-negative eosinophils was determined by flow cytometry. RESULTS:The BALF concentrations of IP10 and Mig were higher in patients with CEP, as well as in patients with sarcoidosis, when compared to healthy controls. The absolute number of CXCR3+ CD4+ T cells was significantly higher in the BALF of patients with sarcoidosis, but not in the patients with CEP, when compared to healthy volunteers. There were higher percentages of CXCR3-expressing eosinophils in the BALF than in the peripheral blood of patients with CEP. CONCLUSIONS:Our findings suggest that IP10 and Mig contribute to the accumulation of CXCR3-expressing eosinophils in the lungs of patients with CEP, and modulate the eosinophilic inflammation of the lung.

背景与目标：

BACKGROUND & AIMS: :Chemokines are recognized as functionally important in many pathological disorders, which has led to increased interest in mechanisms related to the regulation of chemokine receptor (CKR) expression. Known mechanisms for regulating CKR activity are changes in gene expression or posttranslational modifications. However, little is known about CKR with respect to a third regulatory mechanism, which is observed among other seven-transmembrane receptor subfamilies, the concept of differential splicing or processing of heteronuclear RNA. We now report on the discovery of a variant human CKR, CXCR3, resulting from alternative splicing via exon skipping. The observed RNA processing entails a drastically altered C-terminal protein sequence with a predicted four- or five-transmembrane domain structure, differing from all known functional CKR. However, our data indicate that that this splice variant, which we termed CXCR3-alt, despite its severe structural changes still localizes to the cell surface and mediates functional activity of CXCL11.

背景与目标： : 趋化因子在许多病理疾病中被认为具有重要的功能，这导致人们对与趋化因子受体 (CKR) 表达调节有关的机制的兴趣增加。调节CKR活性的已知机制是基因表达的变化或翻译后修饰。然而，关于第三种调节机制的CKR知之甚少，在其他七个跨膜受体亚家族中，观察到这种调节机制，即异核RNA的差异剪接或加工的概念。我们现在报告发现了人类CKR变异体CXCR3，该变异体是通过外显子跳跃产生的。观察到的RNA加工过程需要急剧改变的C末端蛋白序列，具有预测的四或五跨膜结构域结构，与所有已知的功能CKR不同。然而，我们的数据表明，尽管这种严重的结构变化，但我们称之为CXCR3-alt的剪接变体仍位于细胞表面并介导cxcl11的功能活性。

BACKGROUND & AIMS: :We investigated possible cellular receptors for the human CXC chemokine platelet factor-4 variant/CXCL4L1, a potent inhibitor of angiogenesis. We found that CXCL4L1 has lower affinity for heparin and chondroitin sulfate-E than platelet factor-4 (CXCL4) and showed that CXCL10 and CXCL4L1 could displace each other on microvascular endothelial cells. Labeled CXCL4L1 also bound to CXCR3A- and CXCR3B-transfectants and was displaced by CXCL4L1, CXCL4, and CXCL10. The CXCL4L1 anti-angiogenic activity was blocked by anti-CXCR3 antibodies (Abs) in the Matrigel and cornea micropocket assays. CXCL4L1 application in CXCR3(-/-) or in wild-type mice treated with neutralizing anti-CXCR3 Abs, resulted in reduced inhibitory activity of CXCL4L1 on tumor growth and vascularization of Lewis lung carcinoma. Furthermore, CXCL4L1 and CXCL4 chemoattracted activated T cells, human natural killer cells, and human immature dendritic cells (DCs). Migration of DCs toward CXCL4 and CXCL4L1 was desensitized by preincubation with CXCL10 and CXCL11, inhibited by pertussis toxin, and neutralized by anti-CXCR3 Abs. Chemotaxis of T cells, natural killer cells, and DCs is likely to contribute to the antitumoral action. However, the in vivo data indicate that the angiostatic property of CXCL4L1 is equally important in retarding tumor growth. Thus, both CXCR3A and CXCR3B are implicated in the chemotactic and vascular effects of CXCL4L1.

背景与目标： : 我们研究了人类CXC趋化因子血小板因子4变体/CXCL4L1 (一种有效的血管生成抑制剂) 的可能细胞受体。我们发现CXCL4L1对肝素和硫酸软骨素E的亲和力低于血小板因子4 (CXCL4)，并表明CXCL10和CXCL4L1可以在微血管内皮细胞上相互取代。标记的CXCL4L1也与CXCR3A-和CXCR3B-transfectants结合，并被CXCL4L1、CXCL4和cxcl10取代。在Matrigel和角膜微袋试验中，CXCL4L1抗血管生成活性被anti-CXCR3抗体 (Abs) 阻断。CXCL4L1在CXCR3(-/-) 或用中和anti-CXCR3 Abs处理的野生型小鼠中的应用导致CXCL4L1对Lewis肺癌的肿瘤生长和血管形成的抑制活性降低。此外，CXCL4L1和CXCL4化学吸引活化的T细胞，人自然杀伤细胞和人未成熟树突状细胞 (dc)。通过与CXCL10和CXCL11预孵育，使dc向CXCL4和CXCL4L1的迁移脱敏，被百日咳毒素抑制，并被anti-CXCR3 Abs中和。T细胞，自然杀伤细胞和dc的趋化性可能有助于抗肿瘤作用。然而，体内数据表明，CXCL4L1的血管抑制特性在延缓肿瘤生长方面同样重要。因此，CXCR3A和CXCR3B都与CXCL4L1的趋化和血管作用有关。

BACKGROUND & AIMS: :Among the first cells to invade a site of infection, polymorphonuclear neutrophils (PMN) play an important role in the control of numerous infections. While PMN are considered critical for control of acute infections, their role in chronic infections remains less well understood. Here we report that PMN are essential for accurate early granuloma formation during chronic M. tuberculosis infection without influencing mycobacterial growth restriction. The PMN-mediated regulation of granuloma formation depended on chemokines signaling through CXCR3, in particular MIG, as indicated by immune histochemical analysis of lung sections from C57BL/6 wild-type and CXCR3(-/-) mutant mice and supported by microarray transcriptome analysis. Hence, PMN play a central role in regulating the focal granulomatous response in the lung, and this early granuloma formation can be segregated from long-term protection against pulmonary M. tuberculosis infection.

背景与目标： : 在第一批侵入感染部位的细胞中，多形核中性粒细胞 (PMN) 在控制多种感染中起着重要作用。虽然PMN被认为对于控制急性感染至关重要，但它们在慢性感染中的作用仍鲜为人知。在这里，我们报告了PMN对于慢性结核分枝杆菌感染期间准确的早期肉芽肿形成至关重要，而不会影响分枝杆菌的生长限制。PMN介导的肉芽肿形成的调节取决于通过CXCR3 (特别是MIG) 的趋化因子信号传导，如C57BL/6野生型和CXCR3(-/-) 突变小鼠的肺切片的免疫组织化学分析所表明的，并由微阵列转录组分析。因此，PMN在调节肺部局部肉芽肿反应中起着核心作用，这种早期肉芽肿的形成可以与针对肺结核分枝杆菌感染的长期保护措施分开。

BACKGROUND & AIMS: BACKGROUND:Hypersensitivity pneumonitis (HP) is an interstitial lung disease caused by repeated inhalations of finely dispersed organic particles or low molecular weight chemicals. The disease is characterized by an alveolitis sustained by CD8(+) cytotoxic T lymphocytes, granuloma formation, and, whenever antigenic exposition continues, fibrosis. Although it is known that T-cell migration into the lungs is crucial in HP reaction, mechanisms implicated in this process remain undefined. METHODS:Using flow cytometry, immunohistochemistry, confocal microscopy analysis and chemotaxis assays we evaluated whether CXCL10 and its receptor CXCR3 regulate the trafficking of CD8(+) T cells in HP lung. RESULTS:Our data demonstrated that lymphocytes infiltrating lung biopsies are CD8 T cells which strongly stain for CXCR3. However, T cells accumulating in the BAL of HP were CXCR3(+)/IFNgamma(+) Tc1 cells exhibiting a strong in vitro migratory capability in response to CXCL10. Alveolar macrophages expressed and secreted, in response to IFN-gamma, definite levels of CXCL10 capable of inducing chemotaxis of the CXCR3(+) T-cell line. Interestingly, striking levels of CXCR3 ligands could be demonstrated in the fluid component of the BAL in individuals with HP. CONCLUSION:These data indicate that IFN-gamma mediates the recruitment of lymphocytes into the lung via production of the chemokine CXCL10, resulting in Tc1-cell alveolitis and granuloma formation.

背景与目标：