CC family of chemokines

Only the primary sequence of MDC is known. MDC is a member of the CC family of chemokines and shares 28-35% amino acid identity with this group of proteins. This sequence conservation includes the four characteristic cysteines and nine other highly conserved residues (Chang et al., 1997 Godiska et al, 1997). At the C-terminus of MDC there is a stretch of basic residues which is also conserved within the chemokine family and which mediates their ability to interact with heparin. 

Coulin, F., Power C. A., Alouani, S., Peitsch M. C Schroeder J.-M., Moshizuki, M Clark-Lewis, I., and Wells, T. N. C. (1997) Characterisation of macrophage inflammatory protein-5/human CC cytokine-2, a member of the macrophage-inflammatory-protein family of chemokines. Eur. J. Biochem. 248, 507-515. 

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). 

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. 

Chemokines in Leukocyte Trafficking CKs are thought to be centrally involved in leukocyte trafficking and not limited to attraction of monocytes by the CC family and neutrophils by the CXC family. Other functions of the CKs include expression of adhesion molecules, especially for the lymphocytes in both the migratory response and maturation and proliferation. The selective chemoattractant qualities shown by CKs explain the directed migration of each kind of leukocyte or even of subtypes of these cells (as T and B lymphocytes, perhaps even Thl and Th2). Several studies have shown that CC CKs attract T lymphocytes and that CD45R0, memory-phenotype cells are considered to be the main responders. The results, however, have often been contradictory, and the role of lymphocyte activation and proliferation is still unclear. The CC CKs MCP-2, MCP-3, RANTES, MIP-la, MIP-lp, and MCP-1 induce significant, dose-dependent transendothelial chemotaxis of... 

From the functional point of view, chemokines from the CC family in general do not act on neutrophils but attract monocytes, eosinophils, basophils, lymphocytes, and dendritic cells (9,10). (One notable exception is the abil-... 

This receptor, originally cloned as ChemRlS, is part of the family of CC chemokine receptors binding RANTES (CCL5), MIP-la (CCL3), andMIP-l 8 (CCL4) (176-178).CCR5 is expressed on monocytes and some CD4-F T-lymphocyte subsets and its activation leads to chemotaxis of these cells (7). 

The human chemokine system currently includes more than 40 chemokines and 18 chemokine receptors (Table 1). Chemokine receptors are defined by their ability to induce directional migration of cells toward a gradient of a chemo-tactic cytokine (chemotaxis). Chemokine receptors belong to a family of 7 transmembrane domain, G-protein-coupled cell surface receptors (GPCR) and the ligands are classified into four groups (CXC, CC, C, and CX3Q based on the position of the first two cysteines [1, 2]. Chemokine receptors are present on many different cell types. Initially, these receptors were identified on... 

Chemokines are a superfamily of small proteins which play a crucial role in immune and inflammatory reactions and in viral infection (Hedrick and Zlotnik, 1996 Baggi-olini et al, 1997 Rollins, 1997). Most chemokines cause migration of leukocytes, but these molecules also affect angiogenesis, proliferation of hematopoietic precursors, and viral responses. Based on a cysteine motif, a CXC, CC, C and CX3C family have been identified (Fig. 1). CXC (or a) chemokines are active on neutrophils and lymphocytes while CC (or (3) chemokines exert their action on multiple leukocyte subtypes, including monocytes, basophils, eosinophils, T-lymphocytes, dendritic cells (DC) and NK cells, but they are generally inactive on PMN. Eotaxins... 

Chemokines are a family of pro-inflammatory activation-inducible cytokines or small protein signals secreted by cells. Chemokines induce directed chemotaxis in nearby responsive cells and therefore the name c/iemotactic cytokines. Four types of chemokines exist (1) C chemokine the first and the third conserved cysteine residues in the mature protein are missing (2) CC chemokine the first two conserved cysteine residues are adjacent in the mature protein (3) CXC chemokine one amino acid residue separates the first two conserved cysteine residues in the mature protein and (4) CX3C chemokine three amino acid residues separate the first two conserved cysteine residues in the mature protein. 

Chemokines, a sub-family of the cytokines. They are composed of a core domain containing two or three disulfide bonds in a flexible N-terminal domain whose truncation affects the potency of receptor activation. The chemokines are homologous 8- to 10-kDa proteins with 20 to 70% sequence homology. They are subdivided into at least four families based on the relative position of the Cys residues in the mature protein, although only the a- and -chemokines (both of which contain four Cys residues) have been well characterized. In the a-chemokines (CXC chemokines), the first two Cys residues are separated by a single amino acid residue (Cys-Xaa-Cys), whereas in the -chemokines (CC chemokines) the first two Cys residues are adjacent to each other (Cys-Cys). a-Chemokines are roughly 70 to 130 aa in size and are secreted with leader sequences of 20-25 aa which are cleaved before release. Besides the conserved Cys-Xaa-Cys motif near the N-terminus of the protein. 

The rapid pace of chemokine discovery led to a nomenclature crisis, especially in the naming of chemokine ligands. Early reports assigned multiple names to the same chemokine. Fortunately, a new standardized nomenclature has been adopted, largely based on a system previously used for naming of chemokine receptors. Specifically, chemokine receptors are referred to as CC (in the case of the CC chemokine family), CXC (for the CXC family), C (lymphotactin/... 

Chemokines are a family of small, structurally related molecules that play a fundamental role in the development, homeostasis, and function of the immune system (overview provided in Chap. 1). Four closely related subfamilies of chemokines have now been characterized (13,14). Of these, members of two subfamilies in particular have definitively been shown to participate in pulmonary antimicrobial host responses. The ELR+ CXC chemokine family members, which includes CXCLl-8 and CXCL15, have predominant neutrophil stimulatory and chemotactic activities, whereas the ELR CXC chemokines and CC chemokine family exerts predominant chemotactic and/or activating effects on macrophages, specific T cell populations, and/or eosinophils (14). Several lines of evidence would suggest that CXC and CC chemokines represent integral components of antimicrobial host defense. First, the well characterized in vitro and in vivo leuko-... 

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