The CXC Chemokines

The CXC chemokines can be further 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 (1-3). The ELR+ CXC chemokines are chemoattractants for neutrophils and act as potent angiogenic factors (6). In contrast, the ELR CXC chemokines are chemoattractants for mononuclear leukocytes and are potent inhibitors of angiogenesis (6,7). 

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In contrast to the increased angiogenic activity attributable to IL-8/CXCL8, we found a deficiency of the production of the angiostafic factor, IP-lO/CXCLlO, in IPF, as compared to controls (36). Interestingly, IFN-y, a major inducer of IP-IO/CXCLIO from a number of cells, is a known inhibitor of wound repair. 

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McArthur JC (2004) HIV dementia an evolving disease. J Neuroimmunol 157(l-2) 3-10 McArthur JC, Hoover DR, BaceUar H, MUler EN, Cohen BA, Becker JT, Graham NM, McArthur JH, Seines OA, Jacobson LP et al (1993) Dementia in AIDS patients incidence and risk factors. Multicenter AIDS Cohort Study. Neurology 43(ll) 2245-2252 McManus CM, liu JS, Hahn MT, Hua LL, Brosnan CE, Berman JW, Lee SC (2000) Differential induction of chemokines in human microgUa by type I and II interferons. GUa 29(3) 273-280 McQuibban GA, Butler GS, Gong JH, BendaU L, Power C, Clark-Lewis I, OveraU CM (2001) Matrix metaUoproteinase activity inactivates the CXC chemokine stromal ceU-derived factor-1. J Biol Chem 276(47) 43503 3508... 

McQuibban GA, Butler GS, Gong JH, Bendall L, Power C, Clark-Lewis I, Overall CM (2001) Matrix metalloproteinase activity inactivates the CXC chemokine stromal cell-derived factor-1. J Biol Chem 276 43503 3508... 

Oberlin E, Amara A, Bacheleiie F, Bessia C, Virelizier JL, Arenzana-Seisdedos F, Schwartz O, Heard JM, Clark-Lewis I, Legler DF, Loetscher M, Baggiolini M, Moser B (1996) The CXC chemokine SDF-1 is the hgand for LESTR/fusin and prevents infection by T-cell-line-adapted HIV-1. Nature 382 833-835... 

Nagasawa T, Hirota S, Tachibana K, et al. Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature 1996 382 635-8. 

Fu W, Zhang Y, Zhang J, Chen WF. Cloning and characterization of mouse homolog of the CXC chemokine receptor CXCR1. Cytokine 2005 31 9-17. 

Addison CL, Daniel TO, Burdick MD, et al. The CXC chemokine receptor 2, CXCR2, is the putative receptor for ELR+ CXC chemokine-induced angiogenic activity. J Immunol 2000 165 5269-5277. 

Persson-Dajotoy T, Andersson P, Bjartell A, Calafat J, Egesten A. Expression and production of the CXC chemokine growth-related oncogene-alpha by human eosinophils. J Immunol 2003 170(10) 5309-5316. 

Sotsios Y, Whittaker GC, Westwick J, Ward SG. The CXC chemokine stromal cell-derived factor activates a Gi-coupled phosphoinositide 3-kinase in T lymphocytes. J Immunol 1999 163(11) 5954—5963. 

Lacey SF, McDanal CB, Horuk R, Greenberg ML. The CXC chemokine stromal cell-derived factor 1 is not responsible for CD8+ T cell suppression of syncytia-inducing strains of HIV-1. Proc Natl Acad Sci U S A 1997 94(18) 9842-9847. 

Valenzuela-Femandez A, Palanche T, Amara A, et al. Optimal inhibition of X4 HIV isolates by the CXC chemokine stromal cell-derived factor 1 alpha requires interaction with cell surface heparan sulfate proteoglycans. J Biol Chem 2001 276(28) 26550-26558. 

The CXC Chemokines That Display Disparate Angiogenic Activity... 

Based on the structural/functional difference, the members of the CXC chemokine family are unique cytokines in their ability to behave in a disparate manner in the regulation of angiogenesis. The angiogenic members include... 

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. 

Gentilini G, Kirschbaum NE, Augustine JA, Aster RH, Visentin GP. Inhibition of human umbilical vein endothelial cell proliferation by the CXC chemokine, platelet factor 4 (PF4), is associated with impaired downregulation of p21(CiplAVAFl). Blood 1999 93(1) 25—33. 

Germinder H, Sagi-Assif O, Goldberg L, et al. A possible role for CXCR4 and its ligand, the CXC chemokine stromal cell-derived factor-1, in the development of bone marrow metastases in neuroblastoma. J Immunol 2001 167 4747-4757. 

Ludwig A, Schiemann F, Mentlein R, et al. Dipeptidyl peptidase IV (CD26) on T cells cleaves the CXC chemokine CXCL11 (I-TAC) and abolishes the stimulating but not the desensitizing potential of the chemokine. J Leukoc Biol 2002 72 183-191. 

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. 

Human MCP-1 (Fig.l) is a protein of 76 amino acids (MW 8.6 Kd). It contains four cysteines at positions 11, 12, 36 and 52, which are present as two disulfide bonds in the native form (3,4). MCP-1 belongs to a family of proteins, called CC chemokines since they contain adjacent cysteine residues at positions 11 and 12 (5,6). It is also related to another family of chemokines, referred to as the CXC family of chemokines in which the first two cysteine residues are separated by a single amino acid residue(5, 6). The disulfide bonding pattern of MCP-1 has not been determined. The disulfide bonds as shown in Figure 1 have been deduced (3), based on the disulfide bonding pattern determined for the CXC chemokines p-thyroglobulin (7) and IL-8 (8). 

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