Targeting the chemokine network in renal inflammation

Chemokines and their receptors are involved in the pathogenesis of renal diseases. They mediate leukocyte recruitment and activation during initiation as well as progression of renal inflammation. Infiltrating leukocyte subpopulations contribute to renal damage by releasing inflammatory and profibrotic cytokines. All intrinsic renal cells are capable of chemokine secretion on stimulation in vitro. Expression of inflammatory chemokines correlates with renal damage and local accumulation of chemokine receptor-bearing leukocytes in a variety of animal models of renal diseases as well as in human biopsy studies. Chemokines and their respective receptors could represent new targets for therapeutic intervention in renal inflammatory disease states that often tend to progress to end-stage renal disease. This article summarizes the present data on the role of chemokines and their receptors in renal inflammation with special emphasis on our efforts to identify the chemokine receptors CCR1 and CCR2 as promising targets for therapeutic intervention.     

趋化因子及其受体参与癌痛的研究进展

<正>癌痛是指由于肿瘤压迫神经或者肿瘤直接侵犯组织导致的疼痛,这严重降低了癌症患者的生活质量。大多数癌痛是慢性的,病程3个月以上,疼痛程度通常与肿瘤生长或诊疗情况密切联系。癌痛可以分成伤害感受性疼痛及神经病理性疼痛,前者又区分为躯体痛及内脏痛;后者表现为持续出现痛觉过敏症状,这与外周或中枢神经发生病变有关。目前,关于癌痛的诊治尚缺乏有成效的具体方案。近年报告观察到,乳腺癌患者的外周血中CC趋化因子配体2(C-C motif chemokine ligand 2,CCL2)、CCL20、CXC趋化因子配体13(C-X-C motif chemokine ligand 13,CXCL13)等明显升高;在骨癌痛小鼠,     

A burgeoning family of biological mediators: chemokines and chemokine receptors

Chemokines are a superfamily of pro-inflammatory polypeptide cytokines that selectively attract and activate different cell types. Most of its members are small proteins that exhibit conserved cysteines in specific positions. Chemokines activate cells through their binding to shared or unique cell surface receptors which belong to the seven-transmembrane (STM), G-protein-coupled receptors (GPCRs). The large number of chemokines and chemokine receptors are indicative of the importance of these molecules in a variety of pathophysiological conditions.     

Chemokines in rapid leukocyte adhesion triggering and migration

Leukocyte subsets are recruited from the blood to lymphoid and non-lymphoid tissues via a multi-step process that involves distinct adhesive and activation steps. Chemokines, a family of chemotactic cytokines that signal through G-protein-coupled receptors, play critical roles in regulating the leukocyte recruitment cascade. Chemokines can be transported and immobilized on the surface of vascular endothelial cells, where they activate leukocyte subsets expressing specific receptors. Activation signals induce firm adhesion of rolling leukocytes by rapidly upregulating integrin affinity and/or avidity. Chemokines can also direct migration of adherent cells across the endothelium, and control segregation of cells into specific microenvironments within tissues. The regulated expression of chemokines and their receptors is a critical determinant for homing of specialized lymphocyte subsets, and controls both tissue and inflammation-specific immune processes.     

Chemokines on the move: control by the chemokine "interceptors" Duffy blood group antigen and D6

Chemokines drive and direct leukocyte trafficking across the biological barriers. Controlling the microanatomical localization and quantity of chemokines is of fundamental importance in regulating these migratory responses. Here we discuss the emerging roles that two atypical chemokine receptors, Duffy antigen and D6, may play in controlling chemokine movement and how this may impinge on chemokine function. Mechanistically, Duffy antigen and D6 represent a subclass of chemokine internalizing receptors, "interceptors," taking chemokines into nucleated cells in the apparent absence of signaling. The subsequent fate of chemokines, either transport or degradation, may ultimately depend on cell type-specific targeting within the endocytotic pathway.     

趋化因子及其受体的功能

趋化因子是一类控制细胞定向迁移的细胞因子。其功能行使由趋化因子受体介导。通过基因敲除、抗体封闭及转基因技术已证明 ,趋化因子系统在病原体的清除、炎症反应、病原体感染、细胞及器官的发育、创伤的修复、肿瘤的形成及其转移、移植免疫排斥等方面都起着重要的作用。本文综述了趋化因子及其受体的生物学功能的研究进展     

Chemokines and Chemokine Receptors： Their Manifold Roles in Homeostasis and Disease

Chemokines are a superfamily of small proteins that bind to G protein-coupled receptors on target cells and were originally discovered as mediators of directional migration of immune cells to sites of inflammation and injury. In recent years, it has become clear that the function of chemokines extends well beyond the role in leukocyte chemotaxis. They participate in organ development, angiogenesis/angiostasis, leukocyte trafficking and homing, tumorigenesis and metastasis, as well as in immune responses to microbial infection. Therefore, chemokines and their receptors are important targets for modulation of host responses in pathophysiological conditions and for therapeutic intervention of human diseases.     

Role of chemokines in thymocyte development

As they mature, thymocytes migrate to specific regions of the thymus, interact with different types of stromal cells, and thereby receive signals for survival, differentiation, or death. Despite its importance, the molecular control of thymocyte trafficking remains poorly understood. Chemokines and their receptors probably control the homing of T cell progenitors to the thymus, their intrathymic migration, and exit to the periphery. Certain chemokines are abundant in the thymus, and their receptors are expressed during distinct developmental stages. Below, we discuss recent studies of chemokines and their receptors in the thymus, speculating on their function in the frame work of thymocyte trafficking.     

T cells and their partners: The chemokine dating agency

Chemokines and their receptors have long been recognized as key molecules directing leukocyte migration between blood, lymph and tissues. Evidence accumulated in recent years indicates that, in addition to their chemotactic functions, chemokine receptors are highly versatile players fine-tuning immune responses. Chemokine receptors and ligands have been implicated in dendritic-cell maturation, signal transmission at the immunological synapse between T lymphocytes and their cellular partners, and in the polarization of immune responses. These findings identify new roles for chemokines in T-cell triggering and activation of effector functions, and suggest that these small cytokines represent key conductors of adaptive immunity.     

Pathophysiological roles of chemokines in human reproduction: an overview

Chemokines are a group of small cytokines that have an ability to induce leukocyte migration. Chemokines exert their functions by binding and activating specific G protein-coupled receptors. Studies have unveiled pleiotropic bioactivities of chemokines in various phenomena ranging from immunomodulation, embryogenesis, and homeostasis to pathogenesis. In the mammalian reproductive system, chemokines unexceptionally serve in multimodal events that are closely associated with establishment, maintenance, and deterioration of fecundity. The aim of this review is to update the knowledge on chemokines in male and female genital organs, with a focus on their potential pathophysiological roles in human reproduction.     

Knock out models to dissect chemokine receptor function in vivo

Chemokines are a family of small proteins involved in numerous biological processes ranging from hematopoiesis, angiogenesis and lymphocyte trafficking to the extravasation and tissue infiltration of leukocytes in response to inflammatory agents, tissue damage and bacterial or viral infection. Chemokines exert their effects by binding to specific G-protein-coupled seven-transmembrane receptors. In vitro studies suggest that the chemokine system is highly redundant in that most chemokines bind to more than one receptor and most receptors bind multiple chemokines. Therefore, targeted deletion of chemokine receptors has proved to be a useful tool for determining the distinct biological role of these molecules in vivo.     

Chemokines and their role in tumor growth and metastasis

Chemokines are a superfamily of pro-inflammatory polypeptide cytokines that selectively attract and activate different cell types. Many patho-physiological conditions require the participation of chemokines, including inflammation, infection, tissue injury, allergy, cardiovascular diseases, as well as malignant tumors. Chemokines activate cells through their binding to shared or unique cell surface receptors which belong to the seven-transmembrane, G-protein-coupled Rhodopsin superfamily. The role of chemokines in malignant tumors is complex: while some chemokines may enhance innate or specific host immunity against tumor implantation, others may favor tumor growth and metastasis by promoting tumor cell proliferation, migration or neovascularization in tumor tissue. In this review, the authors summarize some of the recent advances in chemokine research and emphasis is made on the effect of chemokines in tumor growth and metastasis.     

Antichemokine immunotherapy for allergic diseases

Chemokines have emerged as critical regulators of leukocyte function and as such represent attractive new targets for the therapy of allergic diseases. Recent studies have revealed important roles for the chemokine family in both the afferent and efferent limbs of the immune system, orchestrating and integrating innate and acquired immune responses. A subset of chemokines including eotaxin-1 (also called CCL11), eotaxin-2 (CCL24), eotaxin-3 (CCL26), MCP (monocyte chemoattractant protein)-3 (CCL7), MCP (monocyte chemoattractant protein)-4 (CCL13), TARC (thymus- and activation-regulated chemokine) (CCL17), and MDC (macrophage-derived chemokine) (CCL22) are highly expressed in allergic inflammation and are regulated by T helper type 2 cytokines. Receptors for these chemokines, including CCR3 (CC chemokine receptor 3), CCR4 (CC chemokine receptor 4) and CCR8 (CC chemokine receptor 8) are expressed on key leukocytes associated with allergic inflammation, such as T helper type 2 cells, eosinophils, mast cells and basophils, establishing a subset of chemokine/chemokine receptors potentially important in allergic inflammation. Recent data using inhibitory antibodies and chemokine antagonists support the concept that interfering with this subset of chemokines and their receptors represents a new approach to allergy immunotherapy.     

Chemokines and chemokine receptors in rheumatoid arthritis

Chemokines are chemotactic cytokines involved in a number of pathological processes, including inflammatory conditions. Chemokines play a role in the pathogenesis of various inflammatory diseases. Based on a burgeoning body of literature, RA was chosen as a prototype to discuss this issue. In this review, the authors give a detailed introduction to the classification and function of chemokines and their receptors. This is followed by a discussion of the role of chemokines and chemokine receptors in RA. Chemokines interact with other inflammatory mediators, such as cytokines. Thus, the regulation of chemokine production and the place of chemokines in the network of inflammatory mediators present in the rheumatoid synovium are also reviewed. Finally, potential strategies using anti-chemokine or anti-chemokine receptor biologicals in anti-rheumatic therapy are discussed.     

Cellular polarization induced by chemokines: a mechanism for leukocyte recruitment?

Chemokines are known to induce leukocyte adhesion to the endothelium and emigration into tissues. Here, Miguel Angel del Pozo and colleagues discuss how these molecules also appear to regulate the redistribution of cell adhesion receptors. Recruitment of adhesion molecules towards a cellular uropod in response to chemokines may represent a novel cooperative mechanism in the recruitment of leukocytes to sites of inflammation.     

趋化因子及其受体与特应性皮炎

趋化因子及其受体在许多疾病的病理生理过程中起着重要作用,是当前医学科研领域的一个热点。近年来趋化因子及其受体在特应性皮炎（AD）中的研究显示CC型趋化因子、CX3C型趋化因子、CXC型趋化因子及其受体与AD的发病机制、临床表现、SCORAD评分、病情活动、治疗反应、治疗监测等关系密切,这对探讨AD发病机制和探索新的治疗方案具有重要意义。     

Role of chemokines and chemokine receptors in the gastrointestinal tract

The pathological association between leucocytes and gastrointestinal diseases has long been recognized. Chemokines are a large family of chemotactic cytokines whose fundamental role is the recruitment of leucocytes to tissues. Although chemokines and their receptors are considered to be mediators of inflammation and tissue injury in several inflammatory diseases, their precise role in the pathophysiology of gastrointestinal diseases remains incompletely understood. Nonetheless, by virtue of their expression and localization at sites of gastrointestinal tissue injury and inflammation, a number of investigators have suggested a vital role for chemokines and their receptors in the pathophysiology of gastrointestinal diseases. This short review examines the role of chemokines and their receptors in the gastrointestinal tract with an emphasis on their involvement in the regulation of intestinal and hepatic inflammation.     

Chemokine receptor oligomerization: a further step toward chemokine function

A broad array of biological responses including cell polarization, movement, immune and inflammatory responses, as well as prevention of HIV-1 infection, are triggered by the chemokines, a family of secreted and structurally related chemoattractant proteins that bind to class A-specific seven-transmembrane receptors linked to G proteins. Chemokines and their receptors should not be considered isolated entities, as they act in complex networks. Chemokines bind as oligomers, or oligomerize after binding to glycosaminoglycans on endothelial cells, and are then presented to their receptors on target cells, facilitating the generation of chemoattractant gradients. The chemokine receptors form homo- and heterodimers, as well as higher order structures at the cell surface. These structures are dynamic and are regulated by receptor expression and ligand levels. Complexity is even greater, as in addition to regulation by cytokines and decoy receptors, chemokine and receptor levels are affected by proteolytic cleavage and other protein modifications. This complex scenario should be considered when analyzing chemokine biology and the ability of their antagonists to act in vivo. Strategies based on blocking or stabilizing ligand and receptor dimers could be alternative approaches that might have broad therapeutic potential.     

Morphine modulates chemokine gene regulation in normal human astrocytes

Chemokines and their receptors have been implicated in the pathogenesis of neuroAIDS. Herein we describe the effects of morphine on the gene expression of beta chemokines and their receptors by primary normal human astrocytes (NHA). Our results show that NHA treated with morphine showed significant downregulation of the gene expression of beta chemokines, MCP-1, and MIP-1 beta, while reciprocally upregulating the expression of their specific receptors, CCR2b, CCR3, and CCR5 as detected by real-time quantitative PCR. These morphine-induced effects on NHA cells were reversed by the opioid mu receptor antagonist, naloxone. Further, our results indicate that morphine-induced effects are mediated via the modulation of MAPK and CREB signaling pathways. These results support our hypothesis that opiates act as co-factors in the neuropathogenesis of HIV infection.     

Chemokines,chemokine receptors and CD4+CD25+ regulatory T cells

The fields of regulatory T (Treg) cells and chemokines/chemokine receptors have progressed rapidly in the last few years. Treg cells, especially CD4⁺CD25⁺ Treg cells, play a critical role in maintaining self-tolerance and immune homeostasis. Chemokines and chemokine receptors are crucial for lymphoid development, homing and immunological regulation. This review will discuss the biological effects of chemokines and chemokine receptors on regulating the migration and development of CD4⁺CD25⁺ Treg cells, and the potential clinical implications of these findings when considering chemokine receptors as therapeutic targets.