CDB15:0000186 CCL11 — CCR5
Experimentally validated in Human; Orthology-inferred in Mouse, Rat, Frog, Chicken, Macaque, Pig, Dog, Cow, Chimp, Sheep
Title
Journal:; Year Published:
Abstract
CCR5 binds multiple CC-chemokines: MCP-3 acts as a natural antagonist.
Blood, 1999; PubMed, Homo sapiens CCL11 — Homo sapiens CCR5
ABSTRACT: CCR5 was first characterized as a receptor for MIP-1alpha, MIP-1beta, and RANTES, and was rapidly shown to be the main coreceptor for M-tropic human immunodeficiency virus (HIV)-1 strains and simian immunodeficiency virus (SIV). Chemokines constitute a rapidly growing family of proteins and receptor-chemokine interactions are known to be promiscuous and redundant. We have therefore tested whether other CC-chemokines could bind to and activate CCR5. All CC-chemokines currently available were tested for their ability to compete with [(125)I]-MIP-1beta binding on a stable cell line expressing recombinant CCR5, and/or to induce a functional response in these cells. We found that in addition to MIP-1beta, MIP-1alpha, and RANTES, five other CC-chemokines could compete for [(125)I]-MIP-1beta binding: MCP-2, MCP-3, MCP-4, MCP-1, and eotaxin binding was characterized by IC(50) values of 0.22, 2.14, 5.89, 29.9, and 21.7 nmol/L, respectively. Among these ligands, MCP-3 had the remarkable property of binding CCR5 with high affinity without eliciting a functional response, MCP-3 could also inhibit the activation of CCR5 by MIP-1beta and may therefore be considered as a natural antagonist for CCR5. It was unable to induce significant endocytosis of the receptor. Chemokines that could compete with high affinity for MIP-1beta binding could also compete for monomeric gp120 binding, although with variable potencies; maximal gp120 binding inhibition was 80% for MCP-2, but only 30% for MIP-1beta. MCP-3 could compete efficiently for gp120 binding but was, however, found to be a weak inhibitor of HIV infection, probably as a consequence of its inability to downregulate the receptor.
Eotaxin is a natural antagonist for CCR2 and an agonist for CCR5.
Blood, 2001; PubMed, Homo sapiens CCL11 — Homo sapiens CCR5
ABSTRACT: Eotaxin is a potent inducer of eosinophil chemotaxis and was considered as a selective ligand of the CC chemokine receptor 3 (CCR3), which is expressed on eosinophils, basophils, and Th2 lymphocytes. This study shows that eotaxin also interacts with CCR2 and CCR5 and can, thus, affect the responses of monocytes, which express both receptors. In human monocytes pretreatment with eotaxin decreased responsiveness to MCP-1, a selective ligand for CCR2, as well as to RANTES and MIP-1 beta, which bind to CCR5. Similar effects were obtained with transfected cells expressing CCR2 or CCR5, but here a difference became apparent: Eotaxin triggered CCR5 at a concentration of 100 nM but not CCR2 even at 1 microM, suggesting an antagonistic effect on this receptor. In agreement with this observation, eotaxin induced internalization of CCR5 but not of CCR2 in human monocytes and transfected cells. Binding studies showed that eotaxin displaces (125) I-MCP-1 from monocytes in a concentration-dependent manner, and functional experiments showed that eotaxin inhibits MCP-1-induced chemotaxis and enzyme release. The results demonstrate that eotaxin is a CCR5 agonist and a CCR2 antagonist. The present findings suggest a role of eotaxin in the fine-tuning of cellular responses occurring at sites of allergic inflammation, in which both MCP-1 and eotaxin are produced. (Blood. 2001;97:1920-1924)