The CC Chemokines

The CC chemokines are chemoattractants for monocytes, T and B lymphocytes, NK cells, dendritic cells, basophils, mast cells, and eosinophils (1-3). The CC chemokines have been found to be produced by an array of cells including monocytes, alveolar macrophages, neutrophils, platelets, eosinophils, mast cells, T cells, B cells, NK cells, keratinocytes, mesangial cells, epithelial cells, hepato-cytes, fibroblasts, smooth muscle cells, mesothelial cells, and endothelial cells (1-3). These cells can produce CC chemokines in response to a variety of factors, including viruses, bacterial products, IL-1, TNF, C5a, LTB4, and IFNs, and appear to be significantly susceptible to suppression by IL-10 (1-3). 

CC chemokine activities are mediated by seven-transmembrane domain, Gprotein-coupled receptors (see Chap. 2). The CC chemokine receptors are structurally homologous. While the transmembrane and the second and third intracellular/ cytoplasmic domains of these receptors are well conserved, the NH2- and COOH- 

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Type 1 T helper cells (Th 1) and type 2 T helper cells (Th2) can be differentially recruited to promote different types of inflammatory reactions. Differential expression of CCRs may be a mechanism for recruitment of Thl and Th2 cells to sites of immune reactivity. Recently, Thl and Th2 cells have been found to express distinct CCRs (61). The expression of a distinct CCR correlated with the response of the cell to a specific chemokine ligand (61). The differential expression of chemokine receptors may orchestrate the trafficking of Thl and Th2 cells. 

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Lau EK, Paavola CD, Johnson Z, et al. Identification of the glycosaminoglycan binding site of the CC chemokine, MCP-1 implications for structure and function in vivo. J Biol Chem 2004 279 22294-305. 

Mayer KL, Stone Ml. NMR solution structure and receptor peptide binding of the CC chemokine eotaxin-2. Biochemistry 2000 39 8382-95. 

TM) GPCRs, and the identification of these two molecules facilitated the discovery of many of the other chemokine receptors. The identification of the two IL8 receptors was followed, shortly after, by the cloning of a receptor for CC chemokines. This receptor was initially called CC-CKR1 (now CCR1) and was shown to promiscuously bind a number of members of the CC chemokine family (6). Subsequent to the identification of these three chemokine receptors, two principal methods have been used to clone the cDNAs for the other currently identified receptors ... 

Alignment of the CC Chemokine Receptors with CCX-CKR (Formerly Called CCR11) and D6... 

KohoutTA, Nicholas SL, Perry SJ, Reinhart G, Junger S, Struthers RS. Differential desensitization, receptor phosphorylation, beta-arrestin recruitment, and ERK1/2 activation by the two endogenous ligands for the CC chemokine receptor 7. J Biol Chem 2004 279(22) 23214-23222. 

Lagane B, Ballet S, Planchenault T, et al. Mutation of the DRY motif reveals different structural requirements for the CC chemokine receptor 5-mediated signaling and receptor endocytosis. Mol Pharmacol 2005 67(6) 1966-1976. 

Odum N, Bregenholt S, Eriksen KW, et al. The CC-chemokine receptor 5 (CCR5) is a marker of, but not essential for the development of human Thl cells. Tissue Antigens 1999 54 572-577. 

Abi-Younes S, Si-Tahar M, Luster AD. The CC chemokines MDC and TARC induce platelet activation via CCR4. Thromb Res 2001 101(4) 279-289. 

Eisner J, Petering H, Hochstetter R, et al. The CC chemokine antagonist Met-RANTES inhibits eosinophil effector functions through the chemokine receptors CCR1 and CCR3. Eur J Immunol 1997 27(ll) 2892-2898. 

Soto H, Wang W, Stricter RM, et al. The CC chemokine 6Ckine binds the CXC chemokine receptor CXCR3. Proc Natl Acad Sci U S A 1998 95(14) 8205—8210. 

Ishida T, Iida S, Akatsuka Y, et al. The CC chemokine receptor 4 as a novel specific molecular target for immunotherapy in adult T-cell leukemia/lymphoma. Clin Cancer Res 2004 10 7529-7539. 

Liang M, Mallari C, Rosser M, et al. Identification and characterization of a potent, selective, and orally active antagonist of the CC chemokine receptor-1. J Biol Chem 2000 275 19000-19008. 

Turner, S.J. Domin, J. Waterfield, M.D. Ward, S.G. Westwick, J. The CC chemokine monocyte chemotactic peptide-1 activates both the class I p85/ pllO phosphatidylinositol 3-kinase and the class II PI3K-C2a. J. Biol. Chem., 273, 25987-25995 (1998)... 

Chemokine receptors are a family of G protein-coupled receptors that contain seven transmembrane domains. Chemokine receptors are present on the cell surface membrane of leukocytes. As was the case for chemokines, these receptors are also divided into four subgroups CCR is specific for CC chemokines, CXCR for CXC chemokines, XCR1 for C chemokines and CX3CR1 for CX3C chemokines. The CC chemokine receptor family has eleven members, the CXC chemokine receptor family has seven members, and both the C chemokine receptor family and the CX3C chemokine receptor family have one member each. The signal transduction is mediated via the standard G protein-dependent pathway. 

E4. Eisner, J., Petering, H., Kimmig, D., Wells, T. N., Proudfoot, A. E., and Kapp, A., The CC chemokine receptor antagonist met-RANTES inhibits eosinophil effector functions. Int. Arch. Allergy Immunol. 118, 462—465 (1999). 

Horuk, R Hesselgesser, R Zhou, Y Faulds, D., Halks-Miller, M Harvey, S., et al. (1998) The CC chemokine 1-309 inhibits CCR8-dependent infection by diverse HIV-1 strains. J. Biol. Chem. 273, 386-391. 

The CC chemokine receptor 5 (CCR5) is of central interest not only because of its involvement in the cellular response to inflammation, but also because it is a key molecule utilized by Human Immunodeficiency Virus type 1 (HIV-1) to gain entry into immune cells (Dragic et al, 2000). Having all the structural and G protein coupling attributes of other... 

No information is available. The genomic structure of MDC has been determined and the intron-exon boundaries are conserved between MDC and other members of the CC chemokine family. In addition the 3 untranslated region of the MDC cDNA is longer than that of other chemokines and includes three Alu repeats (Godiska et al, 1997). 

MDC is most closely related to the CC chemokine TARC. TARC appears to be regulated in a manner... 

Schutyser E, Struyf S, Van Damme J. The CC chemokine CCL20 and its receptor CCR6. Cytok Growth Factor Rev 2003 14 406-26. 

Myocardial ischemia is associated with an inflammatory response that further contributes to myocardial injury and ultimately leads to myocardial healing and scar formation. Myocardial necrosis has been associated with complement activation and free radical generation that trigger cytokine cascades and upregulate chemokines expression. Mononuclear cell chemoattractants, such as the CC chemokines CCL2/Monocyte... 

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