Chemokines—Key Mediators of Inflammation Chemokines are a superfamily ofsmall polypeptides,most of which contain 90–130 amino acid residues.They selectively, and often specifically,control the adhesion,chemotaxis,and activation ofmany types ofleukocyte populations and subpopulations.Consequently,they are major regulators ofleukocyte 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 oflymphocytes,such as determining the correct positioning ofleukocytes 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 ofthe brain and the heart.Members ofthe chemokine family have also been shown to play regulatory roles in the development ofblood 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-,up-regulate the expression ofinflammatory cytokines at sites ofdeveloping inflammation.Chemokines cause leukocytes to move into various tissue sites by inducing the adherence ofthese cells to the vascular endothelium.After migrating into tissues,leukocytes are attracted toward high localized concentrations of chemokines resulting in the targeted recruitment ofphagocytes and effector lymphocyte populations to inflammatory sites.The assembly ofleukocytes at sites ofinfection,orchestrated by chemokines,is an essential part ofmounting 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 oftwo ofthe four invariant cysteine residues,almost all fall into one or the other oftwo distinctive subgroups: C-C subgroupchemokines,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 polypeptide chain traverses the membrane seven times.There are two subgroups ofreceptors,CC receptors (CCRs),which recognize CC chemokines,and CXC receptors (CXCRs),which recognize CXC chemokines.As with cytokines,the interaction between chemokines and their receptors is ofhigh 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 signaltransduction process that generate such potent second messengers as cAMP,IP3,Ca2+,and activated small G proTABLE 15-2Human chemokines and their receptors* Chemokine receptors Chemokines bound by receptor CXC SUBGROUP CXCR1 CXCR2 CXCR3 CXCR4 CXCR5 IL-8, GCP-2 IL-8, Gro-, Gro-, Gro-, NAP-2, ENA-78 IP-10, Mig, I-TAC SDF-1, PBSF BCA-1 CC SUBGROUP CCR1 CCR2 CCR3 CCR4 CCR5 CCR6 CCR7 CCR8 CCR10 MIP-1, RANTES, MCP-2, MIP-5 MCP-1, MCP-2, MCP-3 Eotaxin, RANTES, MCP-2, MCP-3, MCP-4, Eotaxin-2, MIP-5 TARC, RANTES MIP-1RANTES, MIP-1 Exodus-1 ELC 1-309 MCP-1, MCP-2, MCP-3, RANTES BOTH CC AND CXC SUBGROUPS DARC (the Duffy antigen of RBCs) Binds to a number of CC and CXC chemokines *This table lists most known chemokine receptors but not all chemokines. The full names for a number of the chemokines abbreviated in the table are as follows: ELC (Ebl1ligand chemokine); ENA-78(epithelial-cell-derived neutrophil-activating protein); GCP-2(granulocyte c
Posted on: Sun, 21 Jul 2013 07:13:19 +0000
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