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...

Conclusions

Our understanding of atherosclerosis as an inflammatory process has made great strides in the past decade, and it is clear from animal studies as well as clinical data that chemokines play an important role in atherosclerotic vascular disease. Based on the data presented in this chapter, it is possible to construct a theoretical model of how the aforementioned chemokines act in concert with other inflammatory mediators to promote atheroma formation. In response to factors that cause vessel wall...

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...

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...

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...

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...

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...

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...

References

Inflammation in atherosclerosis. Nature 2002 420(6917) 868-874. 2. Ross R. Atherosclerosis an inflammatory disease. N Engl J Med 1999 340(2) 115-126. 3. Reape TJ, Groot PH. Chemokines and atherosclerosis. Atherosclerosis 1999 147(2) 213-225. 4. Charo IF, Ransohoff RM. The many roles of chemokines and chemokine receptors in inflammation. N Engl J Med 2006 354(6) 610-621. 5. Smith JD, Breslow JL. The emergence of mouse models of atherosclerosis and their relevance to clinical research...

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...