Skip to main content
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1998 Oct 15;102(8):1469–1472. doi: 10.1172/JCI4461

Chemokines activate Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor in mammalian cells in culture.

M C Gershengorn 1, E Geras-Raaka 1, A Varma 1, I Clark-Lewis 1
PMCID: PMC508995  PMID: 9788958

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV)/human herpesvirus 8, a virus that appears to be involved in the pathogenesis of Kaposi's sarcoma and primary effusion lymphomas, encodes a G protein-coupled receptor (KSHV-GPCR) that exhibits constitutive signaling. In this report, we show that two chemokines, interleukin 8 (IL-8) and growth-related protein-alpha, activate KSHV-GPCR over constitutive levels. Moreover, as with human receptors, the integrity of the ELR motif of these chemokines is required for activation of KSHV-GPCR. Other residues that are required for IL-8 binding to human chemokine receptors CXCR1 and CXCR2 are important for KSHV-GPCR activation also. Thus, it appears that the ELR binding site and other key domains of ELR chemokine activation have been preserved in the virus KSHV-GPCR. The results suggest that KSHV-GPCR originated from CXCR1 or CXCR2 and that activation of KSHV-GPCR by endogenous chemokines may affect the pathobiology of KSHV infection in humans.

Full Text

The Full Text of this article is available as a PDF (199.2 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Arvanitakis L., Geras-Raaka E., Varma A., Gershengorn M. C., Cesarman E. Human herpesvirus KSHV encodes a constitutively active G-protein-coupled receptor linked to cell proliferation. Nature. 1997 Jan 23;385(6614):347–350. doi: 10.1038/385347a0. [DOI] [PubMed] [Google Scholar]
  2. Baggiolini M., Dewald B., Moser B. Human chemokines: an update. Annu Rev Immunol. 1997;15:675–705. doi: 10.1146/annurev.immunol.15.1.675. [DOI] [PubMed] [Google Scholar]
  3. Baggiolini M., Dewald B., Moser B. Interleukin-8 and related chemotactic cytokines--CXC and CC chemokines. Adv Immunol. 1994;55:97–179. [PubMed] [Google Scholar]
  4. Bais C., Santomasso B., Coso O., Arvanitakis L., Raaka E. G., Gutkind J. S., Asch A. S., Cesarman E., Gershengorn M. C., Mesri E. A. G-protein-coupled receptor of Kaposi's sarcoma-associated herpesvirus is a viral oncogene and angiogenesis activator. Nature. 1998 Jan 1;391(6662):86–89. doi: 10.1038/34193. [DOI] [PubMed] [Google Scholar]
  5. Baldwin E. T., Weber I. T., St Charles R., Xuan J. C., Appella E., Yamada M., Matsushima K., Edwards B. F., Clore G. M., Gronenborn A. M. Crystal structure of interleukin 8: symbiosis of NMR and crystallography. Proc Natl Acad Sci U S A. 1991 Jan 15;88(2):502–506. doi: 10.1073/pnas.88.2.502. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cesarman E., Nador R. G., Bai F., Bohenzky R. A., Russo J. J., Moore P. S., Chang Y., Knowles D. M. Kaposi's sarcoma-associated herpesvirus contains G protein-coupled receptor and cyclin D homologs which are expressed in Kaposi's sarcoma and malignant lymphoma. J Virol. 1996 Nov;70(11):8218–8223. doi: 10.1128/jvi.70.11.8218-8223.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Clark-Lewis I., Dewald B., Geiser T., Moser B., Baggiolini M. Platelet factor 4 binds to interleukin 8 receptors and activates neutrophils when its N terminus is modified with Glu-Leu-Arg. Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3574–3577. doi: 10.1073/pnas.90.8.3574. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Clark-Lewis I., Dewald B., Loetscher M., Moser B., Baggiolini M. Structural requirements for interleukin-8 function identified by design of analogs and CXC chemokine hybrids. J Biol Chem. 1994 Jun 10;269(23):16075–16081. [PubMed] [Google Scholar]
  9. Clark-Lewis I., Moser B., Walz A., Baggiolini M., Scott G. J., Aebersold R. Chemical synthesis, purification, and characterization of two inflammatory proteins, neutrophil activating peptide 1 (interleukin-8) and neutrophil activating peptide. Biochemistry. 1991 Mar 26;30(12):3128–3135. doi: 10.1021/bi00226a021. [DOI] [PubMed] [Google Scholar]
  10. Clore G. M., Appella E., Yamada M., Matsushima K., Gronenborn A. M. Three-dimensional structure of interleukin 8 in solution. Biochemistry. 1990 Feb 20;29(7):1689–1696. doi: 10.1021/bi00459a004. [DOI] [PubMed] [Google Scholar]
  11. Farber J. M. Mig and IP-10: CXC chemokines that target lymphocytes. J Leukoc Biol. 1997 Mar;61(3):246–257. [PubMed] [Google Scholar]
  12. Geras-Raaka E., Varma A., Ho H., Clark-Lewis I., Gershengorn M. C. Human interferon-gamma-inducible protein 10 (IP-10) inhibits constitutive signaling of Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor. J Exp Med. 1998 Jul 20;188(2):405–408. doi: 10.1084/jem.188.2.405. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Hadley T. J., Peiper S. C. From malaria to chemokine receptor: the emerging physiologic role of the Duffy blood group antigen. Blood. 1997 May 1;89(9):3077–3091. [PubMed] [Google Scholar]
  14. Jones S. A., Dewald B., Clark-Lewis I., Baggiolini M. Chemokine antagonists that discriminate between interleukin-8 receptors. Selective blockers of CXCR2. J Biol Chem. 1997 Jun 27;272(26):16166–16169. doi: 10.1074/jbc.272.26.16166. [DOI] [PubMed] [Google Scholar]
  15. Loetscher M., Gerber B., Loetscher P., Jones S. A., Piali L., Clark-Lewis I., Baggiolini M., Moser B. Chemokine receptor specific for IP10 and mig: structure, function, and expression in activated T-lymphocytes. J Exp Med. 1996 Sep 1;184(3):963–969. doi: 10.1084/jem.184.3.963. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Luster A. D. Chemokines--chemotactic cytokines that mediate inflammation. N Engl J Med. 1998 Feb 12;338(7):436–445. doi: 10.1056/NEJM199802123380706. [DOI] [PubMed] [Google Scholar]
  17. Luster A. D., Greenberg S. M., Leder P. The IP-10 chemokine binds to a specific cell surface heparan sulfate site shared with platelet factor 4 and inhibits endothelial cell proliferation. J Exp Med. 1995 Jul 1;182(1):219–231. doi: 10.1084/jem.182.1.219. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Masood R., Cai J., Zheng T., Smith D. L., Naidu Y., Gill P. S. Vascular endothelial growth factor/vascular permeability factor is an autocrine growth factor for AIDS-Kaposi sarcoma. Proc Natl Acad Sci U S A. 1997 Feb 4;94(3):979–984. doi: 10.1073/pnas.94.3.979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Miller G. The oncogenicity of Epstein-Barr virus. J Infect Dis. 1974 Aug;130(2):187–205. doi: 10.1093/infdis/130.2.187. [DOI] [PubMed] [Google Scholar]
  20. Moore B. B., Keane M. P., Addison C. L., Arenberg D. A., Strieter R. M. CXC chemokine modulation of angiogenesis: the importance of balance between angiogenic and angiostatic members of the family. J Investig Med. 1998 Apr;46(4):113–120. [PubMed] [Google Scholar]
  21. Moser B., Dewald B., Barella L., Schumacher C., Baggiolini M., Clark-Lewis I. Interleukin-8 antagonists generated by N-terminal modification. J Biol Chem. 1993 Apr 5;268(10):7125–7128. [PubMed] [Google Scholar]
  22. Nador R. G., Cesarman E., Chadburn A., Dawson D. B., Ansari M. Q., Sald J., Knowles D. M. Primary effusion lymphoma: a distinct clinicopathologic entity associated with the Kaposi's sarcoma-associated herpes virus. Blood. 1996 Jul 15;88(2):645–656. [PubMed] [Google Scholar]
  23. Nakamura S., Murakami-Mori K., Rao N., Weich H. A., Rajeev B. Vascular endothelial growth factor is a potent angiogenic factor in AIDS-associated Kaposi's sarcoma-derived spindle cells. J Immunol. 1997 May 15;158(10):4992–5001. [PubMed] [Google Scholar]
  24. Offermann M. K. Kaposi's sarcoma and HHV-8. Trends Microbiol. 1996 Nov;4(11):419–419. doi: 10.1016/0966-842x(96)84953-5. [DOI] [PubMed] [Google Scholar]
  25. Rangan S. R., Martin L. N., Enright F. M., Abee C. R. Herpesvirus saimiri-induced lymphoproliferative disease in howler monkeys. J Natl Cancer Inst. 1977 Jul;59(1):165–171. doi: 10.1093/jnci/59.1.165. [DOI] [PubMed] [Google Scholar]
  26. Russo J. J., Bohenzky R. A., Chien M. C., Chen J., Yan M., Maddalena D., Parry J. P., Peruzzi D., Edelman I. S., Chang Y. Nucleotide sequence of the Kaposi sarcoma-associated herpesvirus (HHV8). Proc Natl Acad Sci U S A. 1996 Dec 10;93(25):14862–14867. doi: 10.1073/pnas.93.25.14862. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Schütz W., Freissmuth M. Reverse intrinsic activity of antagonists on G protein-coupled receptors. Trends Pharmacol Sci. 1992 Oct;13(10):376–380. doi: 10.1016/0165-6147(92)90116-n. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES