Chemokines And Chemokine Receptors

Chemokines are a large family of structurally homologous cytokines that stimulate leukocyte movement and regulate the migration of leukocytes from the blood to tissues. The name chemokine is a contraction of "chemotactic cytokine." We have already referred to the role of chemo-kines in the organization of lymphoid tissue and now we will describe the general properties of this family of cyto-kines and summarize their multiple roles in innate and adaptive immunity. Table 3-2 summarizes the major features of individual chemokines and their receptors.

Chemokine Structure, Production, and Receptors

There are about 50 human chemokines, all of which are 8- to 12-kD polypeptides that contain two internal disul-fide loops. The chemokines are classified into four families on the basis of the number and location of N-terminal cysteine residues. The two major families are the CC (also called P) chemokines, in which the cysteine residues are adjacent, and the CXC (or a) family, in which these residues are separated by one amino acid. These differences correlate with organization of the subfamilies into separate gene clusters. A small number of chemokines have a single cysteine (C family) or two cysteines separated by three amino acids (CX3C). Chemokines were originally named on the basis of how they were identified and what responses they triggered. More recently, a standard nomenclature, based in part on which receptors the che-mokines bind to (see Table 3-2), is being used. Although there are exceptions, most of the CC chemokines and their receptors mediate recruitment of neutrophils and lymphocytes, and most of the CXC chemokines and their receptors recruit monocytes and lymphocytes.

The chemokines of the CC and CXC subfamilies are produced by leukocytes and by several types of tissue cells, such as endothelial cells, epithelial cells, and fibro-blasts. In many of these cells, secretion of chemokines is induced by recognition of microbes through various cell receptors of the innate immune system discussed in Chapter 4. In addition, inflammatory cytokines, mainly TNF and IL-1, induce chemokine production. Several CC chemokines are also produced by antigen-stimulated T cells, providing a link between adaptive immunity and recruitment of inflammatory leukocytes.

The receptors for chemokines belong to the seven-transmembrane, guanosine triphosphate (GTP)-binding (G) protein-coupled receptor (GPCR) superfamily. These receptors initiate intracellular responses through associated trimeric G proteins. In a resting cell, the receptor-associated G proteins form a stable inactive complex containing guanosine diphosphate (GDP) bound to Ga subunits. Occupancy of the receptor by ligand results in an exchange of GTP for GDP. The GTP-bound form of the G protein activates numerous cellular enzymes, including an isoform of phosphatidylinositol-specific phospholipase C that functions to increase intracellular calcium and activate protein kinase C. The G proteins stimulate cyto-skeletal changes and polymerization of actin and myosin filaments, resulting in increased cell motility. These signals also change the conformation of cell surface inte-grins and increase the affinity of the integrins for their ligands. Chemokine receptors may be rapidly downregu-lated by exposure to the chemokine, and this is a likely mechanism for termination of responses.

TABLE 3-2 Chemokines and Chemokine Receptors

Chemokine

Original Name

Chemokine Receptor

Major Function

CC chemokines

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