The chemokine and chemokine receptor superfamilies and their molecular evolution

The chemokine superfamily includes a large number of ligands that bind to a smaller number of receptors [1,2]. The best known function of the chemokines is the regulation of migration of various cells in the body, hence their name (from 'chemotactic cytokines'). The importance of the chemokines has grown in recent years, as it has become recognized that they are key players in many disease processes, including inflammation, autoimmune disease, infectious diseases (such as HIV/AIDS), and more recently, cancer (in particular in regulating metastasis) [3]. Multiple chemokine ligands can bind to the same receptor; the perceived complexity and promiscuity of receptor binding has often made this field a challenge to understand and given the impression that chemokines lack specific effects. We have now, however, probably identified most human chemokine ligands. The chemokines are small peptides, whereas their receptors are class A G-protein-coupled receptors. They are best known from mammals, but chemokine genes have also been found in chicken, zebrafish, shark and jawless fish genomes, and possible homologs of chemokine receptors have been reported in nematodes. Careful analysis of the members of the superfamily and their receptors shows a logical order to its genomic organization and function, which in turn is the result of evolutionary pressures. Here, we provide a global view of the chemokine and chemokine receptor superfamilies, focusing particularly on the relationship between their evolution and their functions.As shown in Table 1, there are at least 46 chemokine ligands in humans. There are also 18 functionally signaling chemokine receptors (plus one, CXCR7, which has been recently reported as a potential chemokine receptor) and two 'decoy' or 'scavenger' receptors, DARC and D6, which are known to bind several chemokines but do not signal; their function may be to modulate inflammatory responses through their ability to remove chemokine ligands from inflammatory si