A functional IFN-gamma-inducible protein-10/CXCL10-specific receptor expressed by epithelial and endothelial cells that is neither CXCR3 nor glycosaminoglycan

Interferon-gamma -inducible protein-10 (IP-10)/CXCL10 is a CXC chemokine th at attracts T lymphocytes and NK cells through activation of CXCR3, the onl y chemokine receptor identified to date that binds IP-10/CXCL10. We have fo und that several nonhemopoietic cell types, including epithelial and endoth elial cells, have abundant levels of a receptor that binds IP-10/CXCL10 wit h a K-d of 1-6 nM. Surprisingly, these cells expressed no detectable CXCR3 mRNA. Furthermore, no cell surface expression of CXCR3 was detectable by fl ow cytometry, and the binding of I-125-labeled IP-10/CXCL10 to these cells was not competed by the other high affinity ligands for CXCR3, monokine ind uced by IFN-gamma /CXCL9, and I-TAC/CXCL11. Although IP-10/CXCL10 binds to cell surface heparan sulfate glycosaminoglycan (GAG), the receptor expresse d by these cells is not GAG, since the affinity of IP-10/CXCL10 for this re ceptor is much higher than it is for GAG, its binding is not competed by pl atelet factor 4/CXCL4, and it is present on cells that are genetically inca pable of synthesizing GAG. Furthermore, in contrast to IP-10/CXCL10 binding to GAG, IP-10/CXCL10 binding to these cells induces new gene expression an d chemotaxis, indicating the ability of this receptor to transduce a signal . These high affinity IP-10/CXCL10-specific receptors on epithelial cells m ay be involved in cell migration and, perhaps, in the spread of metastatic cells as they exit from the vasculature. (All of the lung cancer cells we e xamined also expressed CXCR4, which has been shown to play a role in breast cancer metastasis.) CXCR3-negative endothelial cells may also use this rec eptor to mediate the angiostatic activity of IP-10/CXCL10, which is also ex pressed by these cells in an autocrine manner.