Chemokine Receptors

Chemokines are a family of low molecular weight secreted proteins that act as leukocyte specific chemoattractants, although they may have additional immunological and non-immunological activities. The greater than 40 known chemokines can be grouped into subfamilies based on structural and genetic considerations. All chemokines (except for lymphotactin) have at least four cysteines in nearly invariant positions. In one major subfamily (CXC or α), the two conserved cysteines in the N-terminal domain are separated by a single amino acid, while in the other major subfamily (CC or β) these two cysteines are adjacent. The other two subfamilies, named C (or γ) and CX3C, are comparatively minor, having only two and one known member(s) in man, respectively. C chemokines are characterized by a single cysteine in the N-terminal domain, and the CX₃C chemokine (known as ‘fractalkine’) has three amino acids interposed between its two amino terminal cysteines.

The genes that encode chemokines tend to cluster with a large cluster of CXC chemokine genes mapping to human chromosome 4q13 and a cluster of CC chemokine genes found on 17q11.1-12. With the rapid pace of discovery of novel chemokines over the course of the last few years, there have been a significant number of reports identifying the same gene, which is typically assigned a different name by the individual investigators. Recently, a standard nomenclature system has been developed and approved by the IUIS/WHO nomenclature committee. In this scheme, the chemokines are named CCL1-28 (C-C chemokine members), CXCL1-16 (CXC chemokine members), CX₃CL1 (fractalkine) and XCL1 and 2 (lymphotactin and SCM-1β).

The basis for leukocyte-specific chemoattraction lies in restricted expression of chemokine receptors (CKR) that are seven transmembrane spanning (7TM) G protein-coupled receptors. So far, six CXC and 11 CC chemokine receptors have been cloned and designated CXCR1-6 and CCR1-11, respectively. In addition, one C and one CX₃C chemokine receptor subtypes have been cloned. Three non-signaling mammalian 7TM chemokine binding proteins have also been identified: the Duffy Antigen Receptor for Chemokines (DARC) that binds both CC and CXC chemokines with high affinity and serves as the receptor for Plasmodium vivax, D6 and CCX CKR. These molecules are thought to function as decoy receptors or chemokine scavengers, negatively regulating chemokine action. Like chemokine genes, chemokine receptor genes also tend to cluster, with a major locus occurring at 3p21.31-32. Most chemokine receptors are coupled through pertussis toxin-sensitive Ga_i proteins, although there is considerable evidence for additional Ga_q coupling in many cases. In addition to the mammalian host chemokine system, many mammalian DNA viruses have also been identified that encode chemokines, functional 7TM chemokine receptors and chemokine receptor-like proteins, presumably pirated from their hosts. Secreted viral chemokine binding proteins with unique structures have also been identified. Finally, some viral proteins function as chemokine mimics. The most notable example is the envelope glycoprotein gp120 of HIV that is able to bind one or more chemokine receptors as an essential step in the cell entry process.

A conundrum in chemokine physiology is the fact that when most chemokine receptors are expressed in heterologous cells, they are found to bind several chemokines with high affinities (K_d <5 nM). Similarly, many individual chemokines bind to multiple receptors. This ligand/receptor promiscuity has led to the suggestion that individual chemokines or individual receptors might not play unique roles in leukocyte physiology or disease. There are however a select number of chemokine receptors that are now recognized to bind a single dedicated ligand. These primarily represent receptors and ligands mediating ‘homeostatic’ functions related to lymphoid organ development and cell population. There is growing evidence that a large number of chemokines may, however, function outside of the simple trafficking paradigm. While classical characterization of chemokine function has centered around cell migration, a large number of chemokines (of all subfamilies) appear to be highly expressed and trigger complex signaling in cells and tissue microenvironments where migration is not a relevant or necessary functionality, and the signaling initiated is peripheral to the migratory phenotype. In addition, chemokine redundancy predicted by in vitro binding patterns appears not to be relevant in vivo. Mice engineered by targeted gene disruption to lack single chemokines or receptors have profoundly abnormal phenotypes indicating that chemokines cannot compensate completely for each other. The basis for this specificity is likely to lie in the spatio-temporal patterns of expression that appear to be unique for each chemokine, in addition to a high degree of divergence in signaling cascades stimulated following receptor ligation.

The Tables below contains accepted modulators and additional information. For a list of additional products, see the "Similar Products" section below.

Abbreviations

6-Ckine/SLC/exodus-2: (CCL21)
BCA-1: B-Lymphocyte Chemoattractant (CXCL13)
CCF18: MIP-1γ (Ccl 9)
CTACK/ESkine: Cutaneous T cell-attracting chemokine (CCL27)
ELC/MIP-3b/exodus 3: (CCL19)
ENA-78: Epithelial Neutrophil Activating Peptide-78 (CXCL5)
Eotaxin: (CCL11)
Fractalkine: (CX3CL1)
GCP-2: Granulocyte Chemotactic Protein-2 (CXCL6)
GRO-α: Growth-Related Oncogene α (CXCL1)
GRO-β: Growth-Related Oncogene β (CXCL2)
GRO-γ: Growth-Related Oncogene γ (CXCL3)
HCC-1/CKβ1/MCIF: Hemofiltrate CC chemokine-1 (CCL14)
HCC-1: Hemofiltrate CC chemokine-1
HCC-2/MIP-5/Lkn-1: Hemofiltrate CC chemokine-2 (CCL15)
HCC-4/LCC-1/CKβ12: Hemofiltrate CC chemokine-4 (CCL16)
I309: (CCL1)
IL-8: Interleukin-8 (CXCL8)
IP-10: Interferon-γ-Inducible Protein-10 (CXCL10)
I-TAC: IFN-Inducible T-cell α-chemoattractant (CXCL11)
MCP-1: Monocyte Chemotactic Protein-1 (CCL2)
MCP-2: Monocyte Chemotactic Protein-2 (CCL8)
MCP-3: Monocyte Chemotactic Protein-3 (CCL7)
MCP-4: Monocyte Chemotactic Protein-4 (CCL13)
MDC: Macrophage-derived Chemokine (CCL22)
MEC: (CCL28)
MIG: Monokine induced by interferon-γ (CXCL9)
MIP-1α: Macrophage Inflammatory Protein-1α (CCL3)
MIP-1β: Macrophage Inflammatory Protein-1β (CCL4)
MIP-3/Ckβ-8: Macrophage Inflammatory Protein-3 (CCL23)
MIP-3α: Macrophage Inflammatory Protein-3α (CCL20)
MIP-3β: Macrophage Inflammatory Protein-3β (CCL19)
mMCP-5: (CCL12)
muMCP-5: (CCL12)
NAP-2: Neutrophil Activating Peptide-2 (CXCL7)
RANTES: Regulated upon Activation Normal T Expressed and Secreted (CCL5)
SDF-1α: Stromal Cell-Derived Factor 1α (CXCL12)
TARC: Thymus Activation-Regulated Chemokine (CCL17)
TECK/CKβ 15: Thymus-expressed chemokine (CCL25)
vMIP-II: Viral macrophage inflammatory protein II

h: human
m: mouse
r: rat