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...

Conclusions

Recent developments have improved our understanding on the role of specific chemokine receptors in the pathophysiology of allograft dysfunction. The data are very encouraging regarding the potential for future therapies directed at CCR5, CCR1, CXCR1 2, and or CXCR3 blockade. Clearly, blocking or modulating the expression of specific chemokines may be an important step in the control of the inflammatory processes leading to chronic transplant damage. Ultimately, chemokine blockades may be most...

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...

References

International Union of Pharmacology. Update on chemokine receptor nomenclature. Pharmacol Rev 2002 54 227-229. 2. Murphy PM, Baggiolini M, Charo IF, et al. International union of pharmacology. XXII. Nomenclature for chemokine receptors. Pharmacol Rev 2000 52 145-176. 3. Rot A, von Andrian UH. Chemokines in innate and adaptive host defense basic chemokinese grammar for immune cells. Annu Rev Immunol 2004 22 891-928. 4. Racusen LC, Solez K, Colvin RB, et al. The Banff 97 working...

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...