Chemokines Key Mediators of Inflammation

Chemokines are a superfamily of small polypeptides, most of which contain 90-130 amino acid residues. They selectively, and often specifically, control the adhesion, chemotaxis, and activation of many types of leukocyte populations and subpopulations. Consequently, they are major regulators of leukocyte traffic. Some chemokines are primarily involved in inflammatory processes, others are constitutively expressed and play important homeostatic or developmental roles. "Housekeeping" chemokines are produced in lymphoid organs and tissues or in non-lymphoid sites such as skin, where they direct normal trafficking of lymphocytes, such as determining the correct positioning of leukocytes newly generated by hematopoiesis and arriving from bone marrow. The thymus constitutively expresses chemokines, and normal B cell lymphopoiesis is also dependent on appropriate chemokine expression. Chemokine-mediated effects are not limited to the immune system. Mice that lack either the chemokine CXCL12 (also called SDF-1) or its receptor (see Table 15-2) show major defects in the development of the brain and the heart. Members of the chemokine family have also been shown to play regulatory roles in the development of blood vessels (angiogenesis), and wound healing.

The inflammatory chemokines are typically induced in response to infection. Contact with pathogens or the action of proinflammatory cytokines, such as TNF-a, up-regulate the expression of inflammatory cytokines at sites of developing inflammation. Chemokines cause leukocytes to move into various tissue sites by inducing the adherence of these cells to the vascular endothelium. After migrating into tissues, leukocytes are attracted toward high localized concentrations of chemokines resulting in the targeted recruitment of phagocytes and effector lymphocyte populations to inflammatory sites. The assembly of leukocytes at sites of infection, orchestrated by chemokines, is an essential part of mounting an appropriately focused response to infection.

More than 50 chemokines and at least 15 chemokine receptors have been described (Table 15-2).The chemokines possess four conserved cysteine residues and based on the position of two of the four invariant cysteine residues, almost all fall into one or the other of two distinctive subgroups:

■ C-C subgroup chemokines, in which the conserved cysteines are contiguous;

■ C-X-C subgroup chemokines, in which the conserved cysteines are separated by some other amino acid (X).

Chemokine action is mediated by receptors whose poly-peptide chain traverses the membrane seven times. There are two subgroups of receptors, CC receptors (CCRs), which recognize CC chemokines, and CXC receptors (CXCRs), which recognize CXC chemokines. As with cytokines, the interac tion between chemokines and their receptors is of high affinity (Ka > 109) and high specificity. However, as Table 15-2 shows, most receptors bind more than one chemokine. For example, CXCR2 recognizes at least six different chemokines, and many chemokines can bind to more than one receptor.

When a receptor binds an appropriate chemokine, it activates heterotrimeric large G proteins, initiating a signal-transduction process that generate such potent second messengers as cAMP, IP3, Ca2+, and activated small G pro-

TABLE 15-2

Human chemokines and their receptors*

Chemokine receptors

Chemokines bound by receptor

CXCSUBGROUP

CXCR1 CXCR2

IL-8, Gro-a, Gro-ß, Gro-y, NAP-2, ENA-78

CXCRS

IP-10, Mig, I-TAC

CXCR4

SDF-1, PBSF

CXCRS

BCA-1

CCSUBGROUP

CCR1

MIP-1, RANTES, MCP-2, MIP-S

CCR2

MCP-1, MCP-2, MCP-3

CCR3

Eotaxin, RANTES, MCP-2, MCP-3, MCP-4, Eotaxin-2, MIP-S

CCR4

TARC, RANTES

CCRS CCR6 CCR7 CCR8 CCR10

Exodus-1

1-309

MCP-1, MCP-2, MCP-3, RANTES

BOTH CC AND CXC SUBGROUPS

BOTH CC AND CXC SUBGROUPS

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