The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1998/7/405/ $5.00
The Journal of Experimental Medicine, Volume 188, Number 2, July 20, 1998 405-408

Brief Definitive Reports

Human Interferon-{gamma}–inducible Protein 10 (IP-10) Inhibits Constitutive Signaling of Kaposi's Sarcoma–associated Herpesvirus G Protein–coupled Receptor

Elizabeth Geras-Raaka*, Anjali Varma*, Hao Ho*, Ian Clark-Lewis{ddagger}, and Marvin C. Gershengorn*

From the * Division of Molecular Medicine, Department of Medicine, Cornell University Medical College and The New York Hospital, New York 10021; and the {ddagger} Biomedical Research Centre, University of British Columbia, Vancouver V6T 1Z4, British Columbia, Canada

A G protein–coupled receptor (GPCR) is encoded within the genome of Kaposi's sarcoma– associated herpesvirus (KSHV)/human herpesvirus 8, a virus that may be involved in the pathogenesis of Kaposi's sarcoma and primary effusion lymphomas. KSHV-GPCR exhibits constitutive signaling activity that causes oncogenic transformation. We report that human interferon (IFN)-{gamma}–inducible protein 10 (HuIP-10), a C-X-C chemokine, specifically inhibits signaling of KSHV-GPCR. In contrast, monokine induced by IFN-{gamma} (HuMig), which like HuIP-10 is an agonist of C-X-C chemokine receptor 3, does not inhibit KSHV-GPCR signaling. Moreover, HuIP-10, but not HuMig, inhibits KSHV-GPCR–induced proliferation of NIH 3T3 cells. These results show that HuIP-10 is an inverse agonist that converts KSHV-GPCR from an active to an inactive state. Thus, a human chemokine inhibits constitutive signaling and cellular proliferation that is mediated by a receptor encoded by a human disease-associated herpesvirus.

Key Words: human monokine induced by interferon {gamma} • C-X-C chemokine receptor 3 • inverseagonist • human herpesvirus 8 • tumorigenesis

Address correspondence to Marvin C. Gershengorn, Cornell University Medical College, 1300 York Ave., Rm. A328, New York, NY 10021. Phone: 212-746-6275; Fax: 212-746-6289; E-mail: mcgersh{at}mail.med.cornell.edu


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