BINDING AND FUNCTIONAL-PROPERTIES OF RECOMBINANT AND ENDOGENOUS CXCR3CHEMOKINE RECEPTORS

IP10 and MIG are two members of the CXC branch of the chemokine superf amily whose expression is dramatically up-regulated by interferon (lFN )-gamma, The proteins act largely on natural killer (NK)-cells and act ivated T-cells and have been implicated in mediating some of the effec ts of IFN-gamma and Lipopolysaccharides (LPSs), as well as T-cell-depe ndent anti-tumor responses. Recently both chemokines have been shown t o be functional agonists of the same G-protein-coupled receptor, CXCR3 , We now report the pharmacological characterization of CXCR3 and find that, when heterologously expressed, CXCR3 binds IP10 and MIG with K- i values of 0.14 and 4.9 nm, respectively. The receptor has very modes t affinity for SDF-1 alpha and little or no affinity for other CXC-che mokines, The properties of the endogenous receptor expressed on activa ted T-cells are similar. Surprisingly, several CC-chemokines, particul arly eotaxin and MCP-4, also compete with moderate affinity for the bi nding of IP10 to CXCR3, Eotaxin does not activate CXCR3 but, in CXCR3- transfected cells, can block IP10-mediated receptor activation. Eotaxi n, therefore, may be a natural CXCR3 antagonist.