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-Inducible Protein-10/CXCL10-Specific Receptor Expressed by Epithelial and Endothelial Cells That Is Neither CXCR3 Nor Glycosaminoglycan1
Department of Adult Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
Interferon-
-inducible protein-10 (IP-10)/CXCL10 is a CXC
chemokine that attracts T lymphocytes and NK cells through activation
of CXCR3, the only chemokine receptor identified to date that binds
IP-10/CXCL10. We have found that several nonhemopoietic cell types,
including epithelial and endothelial cells, have abundant levels of a
receptor that binds IP-10/CXCL10 with a Kd
of 1–6 nM. Surprisingly, these cells expressed no detectable CXCR3
mRNA. Furthermore, no cell surface expression of CXCR3 was detectable
by flow cytometry, and the binding of 125I-labeled
IP-10/CXCL10 to these cells was not competed by the other high affinity
ligands for CXCR3, monokine induced by IFN-/CXCL9, and I-TAC/CXCL11.
Although IP-10/CXCL10 binds to cell surface heparan sulfate
glycosaminoglycan (GAG), the receptor expressed by these cells is not
GAG, since the affinity of IP-10/CXCL10 for this receptor is much
higher than it is for GAG, its binding is not competed by platelet
factor 4/CXCL4, and it is present on cells that are genetically
incapable of synthesizing GAG. Furthermore, in contrast to IP-10/CXCL10
binding to GAG, IP-10/CXCL10 binding to these cells induces new gene
expression and chemotaxis, indicating the ability of this receptor to
transduce a signal. These high affinity IP-10/CXCL10-specific receptors
on epithelial cells may 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 examined also expressed CXCR4, which has
been shown to play a role in breast cancer metastasis.) CXCR3-negative
endothelial cells may also use this receptor to mediate the angiostatic
activity of IP-10/CXCL10, which is also expressed by these cells in an
autocrine manner.
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