Activation of Protein Tyrosine Kinases by Chemokines Relevance to TLymphocyte Migration

Several chemokines have been shown to stimulate tyrosine phosphorylation with evidence for activation of both Src family kinases (40) as well as Jak2 3 (41). However, recent lines of evidence provide compelling evidence that contrary to previous reports, the Jak family kinases are unlikely to play an essential role in chemokine signaling (42). Studies with the zeta-chain associated protein kinase 70 kDa (ZAP-70)-deficient Jurkat leukemic cell line have identified a role for ZAP-70 in CXCR4...

Background of the Chemokine Receptors

Discovery of the Chemokine Receptors It had been suspected for some time that chemokine receptors belonged to the G protein-coupled receptor (GPCR) family. Evidence for this included the previous identification of GPCRs as chemotactic receptors for ligands, such as formal-methionine, leucine, phenylalanine (fMLP), and the sensitivity of chemokine responses to inhibition by pertussis toxin and induction of calcium ion mobilization in response to ligand binding. In 1991, two groups...

Birth of Chemotactic Cytokines or Chemokines

Not more than 20 years ago, a limited number of laboratories around the world were attempting to investigate a small peptide mediator that seemed to have neutrophil chemotactic properties and was thought to be involved in regulation of inflammatory responses. This molecule was identified and From The Receptors The Chemokine Receptors Edited by J. K. Harrison and N. W. Lukacs Humana Press Inc., Totowa, NJ initially termed monocyte-derived neutrophil chemotactic factor (MDNCF)...

Ccr1

CCR1 and CXCR4 expression was observed on multiple myeloma cells (55). The CCR1 and CXCR4 ligands, CCL3 and CXCL12, were expressed at high levels in the bone marrow of patients with multiple myeloma, suggesting that CCR1 and CXCR4 expressed on multiple myeloma cells may mediate their migration to and retention in the bone marrow. CCR1 was the only chemokine receptor found in hepatitis C-induced hepatocellular carcinoma (56). CCL3 is also expressed and may interact in an autocrine fashion with...

Ccr2

Functional CCR2 was expressed on multiple myeloma, and the CCR2 ligands, CCL2, CCL7, and CCL8, were produced by stromal cells cultured from normal and malignant myeloma bone marrow samples (57). Ligand expression likely facilitated the migration of multiple myeloma cells to the bone marrow. CCR2 expression was also examined in liver tumor formation induced by intraportal injection of a murine colon adenocarcinoma cell line (58). Tumor growth occurred at similar rates in wild-type and CCR2- -...

Ccr6

Another chemokine receptor associated with Th2 cells is CCR6. CCR6 is expressed by a subset of dendritic cells, primarily by immature dendritic cells, memory T cells, and B lymphocytes (26-28). The only known chemokine ligand for CCR6, MIP-3a CCL20, is expressed constitutively in some secondary lymphoid tissues, including murine spleen and human tonsils (29,30). The predominant cell source of CCR6 ligands in the lungs is thought to be epithelial cells (31). Primary human bronchoepithelial cells...

Ccr7

CCR7 was highly expressed in breast, melanoma, gastric, non-small cell lung, esophageal, head and neck, and colorectal cancer, as well as in chronic lymphocytic leukemia (2,30-36). Higher expression of CCR7 in each of these malignancies was associated with lymph node metastasis and disease progression. These findings were confirmed in a murine model of melanoma, where forced overexpression of CCR7 in B16 melanoma cells resulted in increased homing to lymph nodes (36). In colorectal carcinoma,...

Ccr9

Epithelial tumor metastasis to the small intestine is rare. CCR9 was highly expressed in all melanoma cells derived from metastatic lesions in the small intestine (65). CCL25 was also expressed in the small intestine and in the thymus. Only malignant cells derived from metastatic lesions in the small intestine responded to CCL25, as determined by receptor downregulation and actin polymerization after binding. This suggests that the CCR9-CCL25 axis guides the metastasis of malignant cell types...

Chang H Kim Summary

Chemokines regulate the process of hematopoiesis by controlling trafficking, proliferation survival, and differentiation of hematopoietic stem and progenitor cells. Unique expression of the chemokine receptor CXCR4 in combination with adhesion molecules very late antigen (VLA)-4, lymphocyte function-associated antigen-1 (LFA-1), and VLA-5 on early hematopoietic stem and progenitor cells makes their homing to bone marrow and seeding the stem cell niche possible. In bone marrow, the CXCL12-CXCR4...

Chemokine Polymorphisms as Predisposing or Prognostic Factors

Genetic variations including single nucleotide polymorphisms (SNPs) in chemokines or chemokine receptors have been linked to diverse inflammatory diseases (28). It is thought that these variations may change the tissue response to injury or the release of chemokines by infiltrating cells. A series of single nucleotide polymorphisms in chemokine and chemokine-receptor genes of the host have been linked to allograft dysfunction. The G allele of the CCL2 -2518 promoter polymorphism is associated...

Chemokine Receptor Dimerization

It has become apparent in recent years that most GPCRs are able to form dimers and other higher order oligomers (68). This conclusion has been reached primarily using heterologous expression systems and by exploiting an array of different methodologies from coimmunoprecipitation and chemical cross-linking to, more recently, biophysical techniques such as bioluminescence resonance energy transfer (BRET) and fluorescence resonance energy transfer (FRET). These techniques have also been used to...

Chemokine Receptors Beyond Migration of Leukocytes

Although the initial focus on this family of molecules concerned their effects on inflammatory leukocyte populations, it nonetheless became clear that che-mokines and their receptors functioned in arenas beyond this aspect of the immune system. One of the prominent early findings that catapulted chemo-kines into the limelight was the discovery that chemokine receptors acted as coreceptors for HIV-1 entry into susceptible cells (discussed in depth in Chapter 13). These included compelling...

Chemokines and Lymphocytes in the Periphery

Central Effector Memory T Cells For T cells, activation by antigen leads to the production of effector memory cells, which show profound differences in patterns of migration compared with na ve cells, related to changes in expression of adhesion molecules and chemo-kine receptors. As described above, T cells require CCR7 to enter lymph nodes and position themselves appropriately within T-cell zones. As expected, therefore, CCR7 is found on all na ve T cells. However, expression of CCR7...

Conclusions

Chemokine receptors represent attractive therapeutic targets and are therefore the focus of intensive investigation. Thus far, much data have been generated regarding the modes of interaction of ligands with the chemokine receptors and on the primary structural basis for receptor function. The next crucial step will involve the determination of a full three-dimensional structure for a chemokine receptor. Once this goal has been achieved, a more complete understanding of the nature of the...

Current Therapy for Treatment

Corticosteroids or immunosuppressive agents have traditionally been used to treat patients with various forms of fibrotic disease, especially those affected by IPF. As previously discussed, the link between chronic inflammation and fibrosis remains controversial, which has driven the exploration for new therapeutic approaches. Recently, innovative attempts have been made to restore Th2 cytokine balance with respect to inflammation. The Th1 cytokine IFN-y has more recently been widely used...

CXCL16 and CXCR6

CXCL16, a recently discovered transmembrane chemokine, has been detected in murine and human atherosclerotic lesions (128,129). Although the precise role of CXCL16 in atherosclerosis remains unclear, studies suggest that it is a candidate molecule in atherosclerosis with multiple functions. Similar to fractalkine, CXCL16 acts as a chemoattractant and adhesion molecule for CXCR6-expressing T lymphocytes and NK cells to sites of inflammation and injury (130-133) independent of integrin activation...

CXCR2CXCL1 Role in Oligodendrocyte Development

CXCR2 is expressed at high levels by specific populations of neurons in multiple regions of the brain (including hippocampus, dentate nucleus of the cerebellum, locus caeruleus, pontine nuclei in the brain stem) and spinal cord. CXCL1 has been shown to be expressed by spinal astrocytes and to be a potent promoter of oligodendrocyte precursor proliferation. In vitro, the proliferative response of immature spinal cord precursors to their major mitogen, platelet-derived growth factor (PDGF), was...

CXCR3CCL21 Inducible System of Microglial Neuronal Communication

CCL21 is a chemokine constitutively expressed in secondary lymphoid organs (lymph nodes and Peyer patches). CCL21 is involved in homing of mature dendritic cells and naive T cells into lymph nodes and is crucial for the formation of secondary lymphoid tissue acting via CCR7. It was recently shown that CCL21 in addition to being part of the peripheral immunosurveillance mechanism is also present in the CNS, with neurons being its primary source (97). In particular, CCL21 is specifically induced...

Cxcr5

Primary central nervous system lymphoma is a rare form of non-Hodgkin lymphoma that rarely spreads beyond the central nervous system. As stated previously, malignant cells of classical Hodgkin lymphoma express CXCR4, CXCR5, and CCR5 that may direct their metastasis to lymph nodes (34). Expression of these receptors on malignant B cells of primary central nervous system lymphomas was confirmed, but expression was restricted to the cytoplasm (54). Primary central nervous system lymphoma may be a...

Development of Hematopoietic Cell Lineage Specific Migration Program

As described above, hematopoietic stem and early progenitor cells uniquely express only CXCR4 and respond to CXCL12 among the 40 chemokines identified so far in chemotaxis (31,34,71). Whereas many mature hematopoietic cell types still retain their responsiveness to CXCL12 after differentiation, some lineages of white blood cells do not respond to CXCL12 but vigorously respond to different chemokines. For example, neutrophils do not respond to CXCL12 (because they do not express CXCR4) but...

Elias Lolis and James W Murphy

This chapter provides an overview of the literature in the field of the structural biology of chemokines. The secondary, tertiary, and quaternary structures as determined by x-ray crystallography and nuclear magnetic resonance are compared among the four chemokine families. The biological significance of chemokine structures is explored through a discussion of additional molecules that interact with the chemokines. Specific interactions of chemokines and their receptors are discussed as are...

Evidence of a Role for Protein Kinase C Activation in TLymphocyte Migration

Activation of phospholipase C (PLC), calcium mobilization, and activation of diacylglycerol (DAG)-dependent PKCs by chemokines have been proposed as regulators of cell adhesion and migration (1,48). However, studies with mice deficient in PLCP1 and P-3 indicated that the PLC pathway is not required for chemotaxis in neutrophils, although its role in T lymphocytes was not investigated (49). Certainly, during LFA-1-mediated locomotion of activated T cells, PKCP1 and PKC5 associate with...

Exploitation of CCR5 and CXCR4 by HIV1 During the Symptomatic Phase of Infection

Although X4 viruses are isolated rarely during the early, asymptomatic period of HIV-1 infection, it has been observed that they appear in approximately 40 to 50 of infected individuals after about 5 years of infection. The phenotypic switch of R5 (NSI) to X4 (SI) strains is usually associated with rapid CD4+ lymphocyte decline and an accelerated progression of AIDS. An increased ability of X4 viral isolates to deplete CD4+ cells has been attributed to the predominant expression of CXCR4 on...

Future Directions

The three-dimensional structures of chemokines have been straightforward to determine. This is due to a number of factors. The small size of these proteins allows for either chemical synthesis or production by recombinant methods. The physiochemical properties of these proteins are generally well-suited for NMR or crystallization. As a consequence, we have learned a lot from these structures. It is much more challenging to structurally characterize complexes of chemokines with GAGs or chemokine...

Gerard J Graham and Robert J Nibbs

To date, all mammalian chemokine receptors and chemokine-binding proteins belong to the seven-transmembrane (7TM)-spanning family of receptors, which are typically, although not exclusively, coupled to G proteins (1). The large G protein-coupled receptor (GPCR) family comprises almost 1000 members in the human genome (2,3) accounting for in excess of 3 of transcribed sequences. This family is subdivided into the class A, B, C, and F S families on the basis of shared motifs, and chemokine...

Importance of Tailoring the Migratory Response

It is important to remember that migrating leukocytes must navigate through complex chemoattractant fields and must migrate from one chemoattractant source to another. Migrating neutrophils have been reported to display memory of their recent environment, such that cells' perception of the relative strength of orienting signals is influenced by their history (55). This allows combinations of chemoattractants to guide leukocytes in a step-by-step fashion to their destinations within tissues, and...

Induction of Primed pDCs by TransHEV Migration

In contrast with mDCs, which are clearly primed by antigens at local inflamed tissues (Figs. 1 and 2), the site of pDC priming is not fully established. We consider that an activated HEV cell is a good candidate to create primed pDCs (13). Because na ve pDC precursors preferentially bind to activated, but not Endothelial cells (Resting HEV cells) E-selectin CD2 ligand CXCL9-binding proteoglycan Endothelial cells (Resting HEV cells) E-selectin CD2 ligand CXCL9-binding proteoglycan Fig. 5. A...

Introduction

Infection and tissue injury induces the migration of cells that results in the innate and or adaptive response. The migration of these cells macrophages, neutrophils, mast cells, basophils, natural killer (NK) cells, and lymphocytes is initiated by a superfamily of secreted proteins known as chemokines. In addition to the proinflammatory response first described for chemokines, some chemokines and their receptors serve other important physiologic functions. These include, but are not limited...

Kim A Neve Series Editor

The Chemokine Receptors, edited by Jeffrey K. Harrison and Nicholas W. Lukacs, 2007 The Serotonin Receptors From Molecular Pharmacology To Human Therapeutics, edited by Bryan L. Roth, 2006 The Adrenergic Receptors In the 21st Century, edited by Dianne M. Perez, 2005 The Melanocortin Receptors, edited by Roger D. Cone, 2000 The GABA Receptors, Second Editon, edited by S.J. Enna and Norman G. Bowery, 1997 The Ionotropic Glutamate Receptors, edited by Daniel T. Monaghan and Robert Wenthold, 1997...

Peter Jon Nelson Stephan Segerer and Detlef Schlondorff

Chemokines exert multiple actions in inflammation, wound healing, and differentiation. Because these processes underlie aspects of the patho-physiology of allograft rejection, chemokine biology has been a major focus of transplantation studies. Although diverse sets of chemokines can be detected in allografts after ischemic reperfusion injury and acute and chronic rejection, recent studies now suggest that relatively few chemo-kine receptors play central roles in the development of transplant...

Pharmaceutical Targeting of Chemokine Receptors

Sofia Ribeiro and Richard Horuk Summary In this chapter, we will give a perspective of in vitro assays used in drug discovery when targeting chemokine receptors. We outline the complexity of the chemokine system and give a historical perspective on the in vitro assays and types of assays used at different stages of discovery, followed by several examples of successes and failures in clinical trials. Finally, we discuss the rationale for continuing, after several failures, to target chemokine...

Preface

G-protein coupled receptors (GPCRs) constitute a large superfamily of proteins that have been historically well represented as drug targets. As such, many of the volumes within The Receptors series have focused their attention on receptor subfamilies in the GPCR superfamily (e.g., adrenergic, serotonergic, dopa-minergic). While chemokine receptors are relatively young, in terms of the knowledge that has accumulated regarding their roles in physiology and pathology, it is clear that this GPCR...

References

Macrophage inflammatory proteins 1 and 2 members of a novel superfamily of cytokines. FASEB J 1989 3 2565-2573. 2. Zlotnick A, Yoshie O. Chemokines a new classification system and their role in immunity. Immunity 2000 12 121-127. 3. Holmes WE, Lee J, Kuang WJ, Rice GC, Wood WI. Structure and functional expression of a human interleukin-8 receptor. Science 1991 253 1278-1280. 4. Murphy PM, Tiffany HL. Cloning of complementary DNA encoding a functional human interleukin-8...

Regulation by Chemokines of Dendritic Cell Migration Dependent Immunity

To better understand the contribution of DC-related chemokines in the generation of immune responses, we investigated the effects of blocking antibodies against various chemokines on the traffic and effector functions of DCs. In the liver disease model, adoptive transfer experiments revealed that CCL21 blockade significantly reduced the number of liver DLN-migrated mDCs (6) (Fig. 4A). Functionally, effective T-cell responses in the DLNs did not occur by blocking CCL21. Instead, a large number...

Regulation of the Homing and Mobilization of Hematopoietic Stem and Progenitor Cells

Homing of HSPCs refers to migration of HSPCs to bone marrow during development or after transplantation. In Tavassoli and Hardy's early review (30) published in 1990 and entitled Molecular basis of homing of intravenously transplanted stem cells to the marrow, it was speculated that Homing is likely to be a complex phenomenon involving multiple interactions at the molecular level. Membrane-associated molecules, as well as extracellular matrix, may be involved. Each of these molecules may act...

Role for CXCR4 in Neutrophil Retention and Mobilization

The bone marrow (BM) contains a large reserve of mature neutrophils. Because neutrophils have a short half-life (t1 2 6 hours), their rate of release from this tissue is a major determinant of the number of circulating neutrophils. In humans, approximately 1011 neutrophils are released from the BM per day (57). Mature neutrophils reside within the hematopoietic compartment of the BM and are intimately associated with stromal cells and or components of extracellular matrix. In response to...

Significance of HIV1 gp120Induced Chemokine Receptor Signaling

An extensive coverage of the chemokine receptors signaling pathways is beyond the scope of the current survey, but some details important for the subsequent discussion will be briefly highlighted. Chemokine receptors are often given as an example of G protein-coupled receptors (GPCRs) that associate exclusively with pertussis toxin (PT)-sensitive Gai proteins however, they may also couple with other subclasses of Ga molecules, such as Gaq or Gas. The mode of these interactions is complex and...

Targeting Chemokine Receptors

Screening of chemokine receptors has focused mostly on ligand displacement assays. These assays use a radiolabeled ligand and cells or membranes expressing the receptor of interest. A small molecule ligand with affinity for the receptor inhibits the binding of the natural radiolabeled ligand (125I). This method allows for the identification of competitive agonists, antagonists, or inverse agonists. Most of the development candidates currently in phase II and above (13) and many small...

Teizo Yoshimura

Neutrophils are the most abundant leukocytes in circulation. They rapidly infiltrate sites of tissue injury and play a critical role in innate immune responses. In addition, they also contribute to the development of adaptive immune responses. Isolation of the human chemokine IL-8 and the cloning of its receptors CXCR1 and CXCR2, followed by the cloning of their orthologues or homologues in animals, have enabled researchers to elucidate the mechanisms of neutrophil trafficking during immune...

The Chemokine System and Arthritis

Quinones, Fabio Jimenez, Carlos A. Estrada, Hernan G. Martiniez, and Seema S. Ahuja 155 11 Chemokine Receptors in Atherosclerosis Maya R. Jerath, Mildred Kwan, Peng Liu, and Dhavalkumar D. Patel 199 12 Chemokine Receptors in Allergic Lung Disease Dennis M. Lindell and Nicholas W. Lukacs 235 13 Chemokine Receptors and HIV AIDS Tzanko S. Stantchev and Christopher C. Broder 259 14 Chemokines and Their Receptors in Fibrosis Glenda Trujillo and Cory M. Hogaboam 295 Michael P. Keane, John...

The Future of Chemokine Receptors Are They Valid Drug Targets

As will be obvious from reading subsequent chapters, chemokine receptors have provided the pharmaceutical industry a rich list of new drug targets. This contention is supported by the clear roles of receptors in a variety of diseases. Technological advances in recombinant DNA methods and the ability to manipulate the genetics of laboratory mice have enhanced our understanding of the roles of specific genes in physiology and pathology. Chemokines and their receptors have not been immune to these...

The Role of Phosphoinositide 3kinases in TLymphocyte Migration

The coordinated and directional trafficking of T lymphocytes in lymphoid and peripheral tissues is a key process in immunosurveillance and immune responses. This involves a multistep adhesion cascade of selectin- or integrin-(and their corresponding vascular ligands) supported rolling, chemokine-mediated integrin activation, and firm integrin-mediated adhesion to the microvasculature endothelium followed by transmigration through the vessel wall and further migration in extravascular tissue...

Tonya C Walser and Amy M Fulton Summary

Many chemokine receptors have now been detected in a variety of malignancies. Considerable data now exist that two receptors, CXCR4 and CCR7, are widely expressed in epithelial cancers and contribute to the ability of some tumors to metastasize. Preclinical studies support a role for these receptors in mediating tumor cell migration, but other functions have also been identified including support of tumor cell proliferation in response to ligand stimulation. Less is known about the function of...

Two Subsets of Nave Dendritic Cells with Distinct Migration and Functional Potentials

The migration pathway described above has been demonstrated only by DCs of myeloid origin. Recent investigations have highlighted the networks of several DC subtypes in the generation of immune responses (8). In mice, there are at least three major functional subtypes of DCs in LNs, myeloid DCs (mDCs CD11b+B220-CD11c+), CD8a+ DCs (CD8a+B220-CD11c+), and plas-macytoid DCs (pDCs B220+CD11c+), which induce distinct types of effector T lymphocytes. mDCs are derived from blood precursors, recruited...

What Is the Significance of Rho GTPases in TLymphocyte Migration

Although PI3K activation seems to be a conserved biochemical response common to most chemokines, it is now clear that this can be a dispensable signal for directional migration of T cells (14,22-24). In many cell types (e.g., endothelial cells, monocytes), the small GTPases Rho, Rac, and cdc42 play key roles in regulating the morphology of migrating cells via effects on the actin cytoskel-eton (5). The effects of Rac and cdc42 are in turn mediated by a family of regulatory proteins including...

Ccr4

CCR4 was expressed in adult T-cell leukemia lymphoma and was associated with skin involvement, and the CCR4 ligand, CCL17, was expressed on normal and inflamed cutaneous endothelia (61). CCR4 expression also characterized other subtypes of T-cell and NK-cell lymphomas. In peripheral T-cell lymphoma, unspecified, CCR4 expression was an independent unfavorable prognostic factor. Interestingly, in this setting, CCR4 mRNA expression positively correlated with FoxP3, a putative marker of T...

The Impact of Migration of Dendritic Cells on Their Effector Functions

Recent findings of DC-mediated peripheral tolerance have changed our view of DC trafficking (3). The significance of steady-state migration of mDCs is the establishment of peripheral tolerance to self-components before exposure to danger signals. In a physiologic condition, a small percentage of naive mDC and pDC precursors exit in the circulation. It is speculated that these cells migrate into the peripheral and lymphoid organs to become tissue-resident immature DCs (na ve DCs). Because 10 of...

Concerted Recruitment of mDCs and pDCs The Role of Chemokines

DC traffic in response to danger signals is dynamic, controlled systemically by cytokines and locally by chemokines (5). The migration pathway is summarized as follows (Fig. 6 steps 1 to 8 in the figure correspond with i to viii in the following text). (i) Danger signals induce local production of TNF-a. (ii) TNF-a released into the circulation promotes systemic inflammation via activation of macrophages and endothelial cells. (iii) Serum TNF-a upregulates Fig. 6. A summary illustration of...

Determination of the Three Dimensional Structure of the Chemokine Receptors

The Need for a Structural Model Approximately 30 to 40 of currently licensed drugs are targeted at GPCRs and thus represent a highly significant source of income for many pharmaceutical companies (80). In the specific context of chemokine receptors, it is clear that they are involved in a number of prominent pathologies and thus represent an important therapeutic target (81). For example, chemokines and their receptors lie at the center of all immune and inflammatory disorders and are...

The Concept of Migration Dependent Dendritic Cell Activation

Dendritic cells (DCs) are bone marrow-derived professional antigen-presenting cells (APCs) (1). The function of DCs depends on their maturation stages progenitors in the bone marrow, precursors in the blood, immature DCs in peripheral tissues, antigen-transporting DCs in the afferent lymphatics, and From The Receptors The Chemokine Receptors Edited by J. K. Harrison and N. W. Lukacs Humana Press Inc., Totowa, NJ mature APCs in lymph nodes (LNs) (2). In a steady-state life cycle, a small number...

Chemokines and Primary Lymphoid Organs 711 Thymus and Developing T Cells

T cells are derived from the common lymphoid progenitors that arise in the bone marrow and migrate to the thymus. Thymocyte precursors are thought to enter at the corticomedullary junction and travel to the subcapsular region before migrating back to the medulla and exiting the thymus. The earliest T cells identified in the thymus are so-called double-negative (DN) thymocytes, as they express neither CD4 nor CD8, and the DN cells can be divided into the progressively more differentiated subsets...

Nicholas W Lukacs and Jeffrey K Harrison

Chemokines were initially discovered in the context of inflammatory pathologies and were the curiosity of a limited number of researchers. Receptors for these cytokine molecules were identified shortly thereafter and determined to be members of the large G protein-coupled receptor (GPCR) superfamily. Collectively, these basic observations provided a framework to understand mechanisms by which leukocyte subsets could migrate into tissues in a specific manner. Nonetheless, as the field evolved,...

Chemokines and Chemokine Receptors

To date, more than 40 chemokines have been identified in humans, and they are further divided into four subfamilies (C, CC, CXC, and CX3C) according to the number and spacing of conserved cysteine residues near the N-terminus (6,7). Chemokines exert their biological functions by binding to high-affinity G protein-coupled receptors a superfamily of seven-transmembrane spanning molecules involved in transducing signals through heterotrimeric GTP-binding proteins. Generally, the G proteins...

Contents

Color 1 The Birth and Maturation of Chemokines and Nicholas W. Lukacs and Jeffrey K. Harrison 1 2 The Structural Biology of Chemokines Elias Lolis and James W. Murphy 9 3 Chemokine Receptors A Structural Overview Gerard J. Graham and Robert J. Nibbs 31 4 Chemokine Signaling in T-Lymphocyte Migration The Role of Phosphoinositide 3-kinase Laura Smith, Adam Webb, and Stephen G. Ward 55 5 Chemokine Receptors and Neutrophil Trafficking Teizo Yoshimura 6 Chemokine Receptors and Dendritic Cell...

Evidence from Human Studies

Experimental animal models have been informative to understand the mechanism of fibrosis and appear to replicate some patterns observed in human disease. Data from human subjects relating to chemokines and chemokine receptor expression in fibrosis correlates with that from animal studies. Human lung epithelial cells from patients with idiopathic pulmonary fibrosis strongly express CCL2 mRNA and its protein product, CCL2, in contrast with those cells from healthy patients (98). Schmidt et al....

Transmission of HIV1 Infection

It is the HIV-1 R5 strains that are predominant during the early and asymptomatic stages of infection and the strains that are also typically present throughout the symptomatic phase as well. Soon after the discovery of the important role CCR5 played as a principal coreceptor for most primary isolates of HIV-1, a particular genetic polymorphism in the CCR5 gene was noted among cohorts of multiply exposed yet uninfected individuals. This mutation was a 32-base- pair deletion (CCR5 A32), which...

Hiroyuki Yoneyama Kenjiro Matsuno and Kouji Matsushima Summary

Dendritic cell (DC) networks dictate peripheral tolerance and immunity in lymph nodes (LNs). The type, timing, location, and interaction of LN-recruited DC subtypes are pivotal and regulated by chemokines. We propose a concept that any DC subtype including myeloid and plasmacy-toid DCs (mDCs and pDCs) is fundamentally categorized by three stages depending on the function and anatomical position naive DC, primed DC, and effector DC. Naive mDC precursors are recruited to inflamed tissues in...

Chemokines and Secondary Lymphoid Organs

CCR7 and Secondary Lymphoid Organs After development in the primary lymphoid organs and egress of mature lymphocytes into the periphery, lymphocytes recirculate through and survey secondary lymphoid organs for their cognate antigens (30). Na ve lymphocytes express CCR7, as well as L-selectin (CD62L) and the integrin lymphocyte function-associated antigen-1 (LFA-1) (CD11a CD18), and respond to the chemokines CCL19 and CCL21 (31-34). The interaction of CCR7 and CCL21 induces integrin...

Chemokine Receptors and Lymphocyte Trafficking

Farber Summary The ordered movement of lymphocytes through and positioning within lymphoid organs and peripheral sites is controlled by adhesion molecules together with chemokines and their receptors. Chemokine-mediated lymphocyte migration is critical for establishing the architecture of lymphoid organs and many aspects of lymphocyte function, including lymphocyte development, activation, and effector activity. Of the 19 chemokine receptors described in humans,...

Chemokines and the Directed Recruitment of Leukocytes into Allografts

Until recently, it has been difficult to dissect the relative role of each chemokine in the inflammatory processes leading to allograft rejection, especially as many chemokines and chemokine receptors are seemingly redundant (2,8). Indeed, during allograft rejection, the expression of many chemokines and chemokine receptors can be detected in the allograft only a few of which represent viable targets for therapeutic intervention (5,6). Chemokine regulation of leukocyte migration occurs within a...

Michael P Keane John A Belperio and Robert M Strieter

Angiogenesis is the process of new blood vessel growth and is a critical biological process under both physiologic and pathologic conditions. Angiogenesis can occur under physiologic conditions that include embryogenesis and the ovarian menstrual cycle. In contrast, pathologic angiogenesis is associated with chronic inflammation chronic fibroproliferative disorders and tumorigenesis of cancer. Similarly, aberrant angiogenesis associated with chronic inflammation fibroproliferative disorders is...

Nicholas W Lukacs PhD

Department of Pathology and Graduate Program in Immunology University of Michigan Medical School Ann Arbor, MI 2007 Humana Press Inc., a division of Springer Science+Business Media, LLC 999 Riverview Drive, Suite 208 Totowa, New Jersey 07512 For additional copies, pricing for bulk purchases, and or information about other Humana titles, contact Humana at the above address or at any of the following numbers Tel. 973-256-1699 Fax 973-256-8341, E-mail order humanapr.com or visit our Website http...

The Immunobiology of Vascularized Allografts

The transplantation of solid organs such as lung, liver, kidney, and heart is only possible in the context of suppression of the immune response, specifically the adaptive T-cell response (10). The three basic effector mechanisms involved in allograft rejection are production of alloantibodies (against both major histocompatibility complex (MHC) and non-MHC antigens), delayed-type hypersensitivity, and T-cell toxicity. The pathophysiologic processes can further be categorized based in part on...

T

Biochemical signals used during chemokine-mediated lymphocyte migration. Engagement of a typical Gai-coupled chemokine receptor leads primarily to activation of the Rac-specific guanine nucleotide exchange factor (GEF) DOCK-2. The mechanism by which GPCRs couple to DOCK-2 is unclear, but Rho GTPases are implicated in other systems. In addition, receptor engagement also triggers activation of PI3Ks. The y isoform of p110 is the major PI3K isoform activated, but other class 1A p110...

HIV1 Tropism

Genotypic and phenotypic variation is a hallmark of HIV-1 infection. The ability of the virus to infect different cell types varies from one isolate to the next and is referred to as cellular tropism, or cytotropism. Initially, HIV-1 isolates were classified as M-tropic (able to infect primary human macrophages and CD4+ lymphocytes), T-tropic (infecting primary CD4+ T cells and T cell lines but not macrophages), and dual-tropic (capable of infecting all three cellular targets). In general,...

Tzanko S Stantchev and Christopher C Broder

There have been tremendous advances made toward our understanding of chemokine receptor biology over the past decade. Much of the research conducted in this area was fueled by discoveries that certain chemokine receptor ligands (chemokines) could specifically block human immunodeficiency virus type 1 (HIV-1) infection and that certain chemokine receptors were the long-sought coreceptors that, together with CD4, were required for the productive entry of HIV-1, HIV-2, and simian immunodeficiency...

Chemokine Structures

Tables 2 and 3 present lists of the known three-dimensional structures of human and viral chemokines. Virtually all chemokine structures, regardless of family, have the same monomeric structure. A flexible N-terminal region precedes the first cysteine and is involved in receptor activation. After the N-terminal region is the 10- to 20-residue N-terminal loop that is generally involved in receptor specificity, a short 310 helix, a P-sheet composed of three antiparallel P-strands, and a...

Chemokines and Their Receptors in Fibrosis

Hogaboam Tissue fibrosis, which results in the destruction of normal organ function, is a leading cause of morbidity and mortality. Current strategies for treating fibrosis have been unsuccessful, largely because of the difficulty in distinguishing whether inflammatory or fibrogenic events sustain the progression of the disease. The causes of fibrosis are diverse regardless of the tissue involved, and the common features include the sequential recruitment of...

Fibrosis Is It Linked to Inflammation

The primary causes of fibrosis are diverse and include toxic vapors, inorganic dusts, drugs, and radiation (4,6). Physical or chemical injuries and immunologic disorders can lead to cutaneous fibrosis such as keloids, hypertrophic scars, and scleroderma (systemic sclerosis) (4). Alcohol and viral infections are major causes of hepatic fibrosis, and glomerulonephritis, diabetic mellitus, and hypertension are major causes of renal scarring (4,6). Diffuse cardiac fibrosis is one of the major...

CXC Chemokine Receptors 1621 CXCR4

Muller et al. performed a comprehensive examination of chemokine receptor expression on a series of breast cancer and melanoma cell lines (2). Using quantitative RT-PCR and specific probes for CXCR1-5, CCR1-10, CX3CR1, and XCR1, seven breast cancer cell lines expressed mRNA primarily for CXCR4, CXCR2, and CCR7. In comparison with normal mammary epithelial cultures, CXCR4 and CCR7 were consistently elevated in malignant cell lines. Like breast cancer cell lines, melanoma cell lines also...

Primary Structural Determinants of Chemokine Receptor Function

Cysteines in Chemokine Receptor Structure and Function Data from studies with other GPCRs have highlighted the importance of extracellular cysteines in ligand binding and the maintenance of the conformational integrity of the receptors. There are typically four conserved cysteine residues found on extracellular domains of chemokine receptors (see Figure 1 and Tables 2 and 3) one on the amino-terminus and one on each of the three extracellular loops. It is clear that the cysteines on...

Signaling by Chemokine Receptors 341 Receptor Structure and Signal Transduction

Chemokine receptors and other GPCRs are thought to undergo a conformational change upon ligand binding that drives intracellular signaling (47). The agonist is envisaged to stabilize the active conformation, a modified receptor structure that contains critical alterations in the nature of its interaction with second messenger systems, such as heterotrimeric G-protein complexes. The DRY box in the second intracellular loop, along with the single letter amino acid code for asparagine, proline X-X...

Th1 versus Th2 Chemokine Receptor Profiles

Although there are exceptions to the rule (1), differential chemokine receptor expression tends to be present under Th1 and Th2 inflammatory conditions. Under Th1 conditions, CXCR3 and, to a lesser extent, CCR5 predominate. Conversely, under Th2 conditions, CCR3, CCR4, and CCR8 are preferentially expressed. Thus, under Th1-promoting conditions, CXCR3 ligands including 10 kDa interferon-gamma-induced protein (IP-10) CXCL9, gamma interferon-induced monokine (MIG) CXCL10, and interferon-inducible...

How Successful Have These Approaches Been

CCR5 Antagonists for HIV The Success Story Maybe The finding, several years ago, that the chemokine receptors CCR5 and CXCR4 were major coreceptors, along with CD4, for human immunodeficiency virus (HIV-1) invasion resulted in the rapid development of chemokine receptor antagonists by the pharmaceutical industry, and CCR5 antagonists for the treatment of HIV have progressed the fastest through the clinic (12). HIV-1 resistance exhibited by some exposed but uninfected individuals is due,...

The CXC Chemokines

The CXC chemokines can be divided into two groups on the basis of a structure function domain consisting of the presence or absence of three amino acid residues (Glu-Leu-Arg ELR motif) that precedes the first cysteine amino acid residue in the primary structure of these cytokines. The ELR+ CXC che-mokines are chemoattractants for neutrophils and act as potent angiogenic factors (6). In contrast, the ELR-CXC chemokines are chemoattractants for mononuclear cells and are potent inhibitors of...

How Relevant Are Heterodimers as Disease Targets

It is now well accepted that many GPCRs can exist as homo- and heterodimers. However, the physiologic relevance of receptor dimerization is still largely unknown. It is clear from some studies that GPCR dimerization can alter ligand function for example, a number of anti-parkinsonian agents have been reported to have a higher affinity with dopamine D3 D2 heterodimers than with the equivalent homodimers (31). Another example is provided by the receptors CB1 (cannabinoid) and orexin. When these...

CCL2 MCP1 and CCR2

Chemokine Receptor Ccr2 Responses

Recruitment of mononuclear leukocytes to the atherosclerotic lesion is a critical step in both the initial development and further progression of the plaque. Monocyte chemoattractant protein (MCP)-1, CCL2, is a member of the CC chemokine family and is a potent monocyte and lymphocyte chemoattrac-tant (22). It is produced by various cell types in the arterial wall including endothelial cells (23,24), smooth muscle cells (25), and fibroblasts (23). CCL2 initiates signal transduction through...

Ligand Binding by Chemokine Receptors

Chemokine Receptor Ligand Binding Profiles On one level, chemokine receptor biology and biochemistry is easy to understand in that CCRs bind CC chemokines, CXCRs bind CXC chemokines, and the XCR and CX3CR receptors bind their respective ligand partners. There are a few reported exceptions to this general rule (8), but the only mammalian che-mokine receptor that comprehensively binds ligands from more than one subfamily is the DARC receptor, which binds a number of inflammatory CC and CXC...

Three Dimensional Structures of Viral Chemokines

A-helices are packed against the P-sheet and provide interactions that stabilize the dimeric structure. This structure resembles the major histocompatibility complex MHC with the exception that CXCL8 is much smaller and compact and does not contain a major groove as is present between the MHC a-helices, which provides the antigen binding site. The oligomeric structures of specific CXC chemokines, as well as CC chemokines, are not always the same in nuclear magnetic resonance NMR and crystal...

Chemokine Receptor Interactions

The identification of GPCRs as chemokine receptors led to the expectation that small-molecule antagonists or agonists would be easier to identify and develop into drugs for diseases caused by dysregulation of these proteins 43 . This expectation was complicated by the realization that chemokine receptors display a great deal of redundancy, with different receptors having overlapping activities. Moreover, multiple chemokines can activate the same receptor. The possibility was suggested that...

Contributors

Ahuja South Texas Veterans Health Care System, Audie L. Murphy Division, San Antonio, Veterans Administration Center for Research on AIDS and HIV-1 Infection, San Antonio, TX and Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA John A. Belperio Department of Medicine, Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA, USA Christopher C....