Skip to main content
NCBI home page
Journal of Virology logoLink to Journal of Virology
. 1997 Jan;71(1):839–842. doi: 10.1128/jvi.71.1.839-842.1997

Human herpesvirus 8 encodes a homolog of interleukin-6.

F Neipel 1, J C Albrecht 1, A Ensser 1, Y Q Huang 1, J J Li 1, A E Friedman-Kien 1, B Fleckenstein 1
PMCID: PMC191128  PMID: 8985427

Abstract

Kaposi's sarcoma is a multifocal lesion that is reported to be greatly influenced by cytokines such as interleukin-6 (IL-6) and oncostatin M. DNA sequences of a novel human gammaherpesvirus, termed human herpesvirus 8 (HHV-8) or Kaposi sarcoma-associated herpesvirus, have been identified in all epidemiological forms of Kaposi's sarcoma with high frequency. The presence of HHV-8 DNA is also clearly associated with certain B-cell lymphomas (body cavity-based lymphomas) and multicentric Castleman's disease. Sequence analysis of a 17-kb fragment revealed that adjacent to a block of conserved herpesvirus genes (major DNA-binding protein, glycoprotein B, and DNA polymerase), the genome of HHV-8 encodes structural homolog of IL-6. This cytokine is involved not only in the pathogenesis of Kaposi's sarcoma but also in certain B-cell lymphomas and multicentric Castleman's disease. The viral counterpart of IL-6 (vIL-6) has conserved important features such as cysteine residues involved in disulfide bridging or an amino-terminal signal peptide. Most notably, the region known to be involved in receptor binding is highly conserved in vIL-6. This conservation of essential features and the remarkable overlap between diseases associated with HHV-8 and diseases associated with IL-6 disregulation clearly suggest that vIL-6 is involved in HHV-8 pathogenesis.

Full Text

The Full Text of this article is available as a PDF (163.3 KB).

Selected References

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

  1. Albrecht J. C., Fleckenstein B. New member of the multigene family of complement control proteins in herpesvirus saimiri. J Virol. 1992 Jun;66(6):3937–3940. doi: 10.1128/jvi.66.6.3937-3940.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Albrecht J. C., Nicholas J., Biller D., Cameron K. R., Biesinger B., Newman C., Wittmann S., Craxton M. A., Coleman H., Fleckenstein B. Primary structure of the herpesvirus saimiri genome. J Virol. 1992 Aug;66(8):5047–5058. doi: 10.1128/jvi.66.8.5047-5058.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Albrecht J. C., Nicholas J., Cameron K. R., Newman C., Fleckenstein B., Honess R. W. Herpesvirus saimiri has a gene specifying a homologue of the cellular membrane glycoprotein CD59. Virology. 1992 Sep;190(1):527–530. doi: 10.1016/0042-6822(92)91247-r. [DOI] [PubMed] [Google Scholar]
  4. Altschul S. F., Gish W., Miller W., Myers E. W., Lipman D. J. Basic local alignment search tool. J Mol Biol. 1990 Oct 5;215(3):403–410. doi: 10.1016/S0022-2836(05)80360-2. [DOI] [PubMed] [Google Scholar]
  5. Amaral M. C., Miles S., Kumar G., Nel A. E. Oncostatin-M stimulates tyrosine protein phosphorylation in parallel with the activation of p42MAPK/ERK-2 in Kaposi's cells. Evidence that this pathway is important in Kaposi cell growth. J Clin Invest. 1993 Aug;92(2):848–857. doi: 10.1172/JCI116659. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bailer R. T., Lazo A., Ng-Bautista C. L., Hout B. L., Ness G. M., Hegtvedt A. K., Blakeslee J. R., Stephens R. E., Brierley G. P., Mallery S. R. Comparison of constitutive cytokine release in high and low histologic grade AIDS-related Kaposi's sarcoma cell strains and in sera from HIV+/KS+ and HIV+/KS- patients. J Interferon Cytokine Res. 1995 May;15(5):473–483. doi: 10.1089/jir.1995.15.473. [DOI] [PubMed] [Google Scholar]
  7. Cai J., Gill P. S., Masood R., Chandrasoma P., Jung B., Law R. E., Radka S. F. Oncostatin-M is an autocrine growth factor in Kaposi's sarcoma. Am J Pathol. 1994 Jul;145(1):74–79. [PMC free article] [PubMed] [Google Scholar]
  8. Chang Y., Cesarman E., Pessin M. S., Lee F., Culpepper J., Knowles D. M., Moore P. S. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science. 1994 Dec 16;266(5192):1865–1869. doi: 10.1126/science.7997879. [DOI] [PubMed] [Google Scholar]
  9. Chang Y., Ziegler J., Wabinga H., Katangole-Mbidde E., Boshoff C., Schulz T., Whitby D., Maddalena D., Jaffe H. W., Weiss R. A. Kaposi's sarcoma-associated herpesvirus and Kaposi's sarcoma in Africa. Uganda Kaposi's Sarcoma Study Group. Arch Intern Med. 1996 Jan 22;156(2):202–204. [PubMed] [Google Scholar]
  10. Dupin N., Grandadam M., Calvez V., Gorin I., Aubin J. T., Havard S., Lamy F., Leibowitch M., Huraux J. M., Escande J. P. Herpesvirus-like DNA sequences in patients with Mediterranean Kaposi's sarcoma. Lancet. 1995 Mar 25;345(8952):761–762. doi: 10.1016/s0140-6736(95)90642-8. [DOI] [PubMed] [Google Scholar]
  11. Ehlers M., Grötzinger J., de Hon F. D., Müllberg J., Brakenhoff J. P., Wollmer A., Rose-John S. Residues 77-95 of the human interleuken-6 protein are responsible for receptor binding and residues 41-56 for signal transduction. Ann N Y Acad Sci. 1995 Jul 21;762:400–402. doi: 10.1111/j.1749-6632.1995.tb32347.x. [DOI] [PubMed] [Google Scholar]
  12. Ekida T., Nishimura C., Masuda S., Itoh S., Shimada I., Arata Y. A receptor-binding peptide from human interleukin-6: isolation and a proton nuclear magnetic resonance study. Biochem Biophys Res Commun. 1992 Nov 30;189(1):211–220. doi: 10.1016/0006-291x(92)91546-3. [DOI] [PubMed] [Google Scholar]
  13. Fossiez F., Djossou O., Chomarat P., Flores-Romo L., Ait-Yahia S., Maat C., Pin J. J., Garrone P., Garcia E., Saeland S. T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines. J Exp Med. 1996 Jun 1;183(6):2593–2603. doi: 10.1084/jem.183.6.2593. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gao S. J., Kingsley L., Li M., Zheng W., Parravicini C., Ziegler J., Newton R., Rinaldo C. R., Saah A., Phair J. KSHV antibodies among Americans, Italians and Ugandans with and without Kaposi's sarcoma. Nat Med. 1996 Aug;2(8):925–928. doi: 10.1038/nm0896-925. [DOI] [PubMed] [Google Scholar]
  15. Honess R. W., Craxton M. A., Williams L., Gompels U. A. A comparative analysis of the sequence of the thymidine kinase gene of a gammaherpesvirus, herpesvirus saimiri. J Gen Virol. 1989 Nov;70(Pt 11):3003–3013. doi: 10.1099/0022-1317-70-11-3003. [DOI] [PubMed] [Google Scholar]
  16. Huang Y. Q., Li J. J., Kaplan M. H., Poiesz B., Katabira E., Zhang W. C., Feiner D., Friedman-Kien A. E. Human herpesvirus-like nucleic acid in various forms of Kaposi's sarcoma. Lancet. 1995 Mar 25;345(8952):759–761. doi: 10.1016/s0140-6736(95)90641-x. [DOI] [PubMed] [Google Scholar]
  17. Huang Y. Q., Li J. J., Kim K. S., Nicolaides A., Zhang W. G., Le J., Poiesz B. J., Friedman-Kien A. E. HIV-1 infection and modulation of cytokine and growth factor expression in Kaposi's sarcoma-derived cells in vitro. AIDS. 1993 Mar;7(3):317–322. doi: 10.1097/00002030-199303000-00002. [DOI] [PubMed] [Google Scholar]
  18. Jung J. U., Stäger M., Desrosiers R. C. Virus-encoded cyclin. Mol Cell Biol. 1994 Nov;14(11):7235–7244. doi: 10.1128/mcb.14.11.7235. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Kedes D. H., Operskalski E., Busch M., Kohn R., Flood J., Ganem D. The seroepidemiology of human herpesvirus 8 (Kaposi's sarcoma-associated herpesvirus): distribution of infection in KS risk groups and evidence for sexual transmission. Nat Med. 1996 Aug;2(8):918–924. doi: 10.1038/nm0896-918. [DOI] [PubMed] [Google Scholar]
  20. Louie S., Cai J., Law R., Lin G., Lunardi-Iskandar Y., Jung B., Masood R., Gill P. Effects of interleukin-1 and interleukin-1 receptor antagonist in AIDS-Kaposi's sarcoma. J Acquir Immune Defic Syndr Hum Retrovirol. 1995 Apr 15;8(5):455–460. doi: 10.1097/00042560-199504120-00004. [DOI] [PubMed] [Google Scholar]
  21. Masood R., Lunardi-Iskandar Y., Jean L. F., Murphy J. R., Waters C., Gallo R. C., Gill P. Inhibition of AIDS-associated Kaposi's sarcoma cell growth by DAB389-interleukin 6. AIDS Res Hum Retroviruses. 1994 Aug;10(8):969–975. doi: 10.1089/aid.1994.10.969. [DOI] [PubMed] [Google Scholar]
  22. Miles S. A., Martínez-Maza O., Rezai A., Magpantay L., Kishimoto T., Nakamura S., Radka S. F., Linsley P. S. Oncostatin M as a potent mitogen for AIDS-Kaposi's sarcoma-derived cells. Science. 1992 Mar 13;255(5050):1432–1434. doi: 10.1126/science.1542793. [DOI] [PubMed] [Google Scholar]
  23. Miles S. A. Pathogenesis of human immunodeficiency virus-related Kaposi's sarcoma. Curr Opin Oncol. 1992 Oct;4(5):875–882. doi: 10.1097/00001622-199210000-00010. [DOI] [PubMed] [Google Scholar]
  24. Miles S. A., Rezai A. R., Salazar-González J. F., Vander Meyden M., Stevens R. H., Logan D. M., Mitsuyasu R. T., Taga T., Hirano T., Kishimoto T. AIDS Kaposi sarcoma-derived cells produce and respond to interleukin 6. Proc Natl Acad Sci U S A. 1990 Jun;87(11):4068–4072. doi: 10.1073/pnas.87.11.4068. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Moore P. S., Chang Y. Detection of herpesvirus-like DNA sequences in Kaposi's sarcoma in patients with and without HIV infection. N Engl J Med. 1995 May 4;332(18):1181–1185. doi: 10.1056/NEJM199505043321801. [DOI] [PubMed] [Google Scholar]
  26. Moore P. S., Gao S. J., Dominguez G., Cesarman E., Lungu O., Knowles D. M., Garber R., Pellett P. E., McGeoch D. J., Chang Y. Primary characterization of a herpesvirus agent associated with Kaposi's sarcomae. J Virol. 1996 Jan;70(1):549–558. doi: 10.1128/jvi.70.1.549-558.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Murakami-Mori K., Taga T., Kishimoto T., Nakamura S. AIDS-associated Kaposi's sarcoma (KS) cells express oncostatin M (OM)-specific receptor but not leukemia inhibitory factor/OM receptor or interleukin-6 receptor. Complete block of OM-induced KS cell growth and OM binding by anti-gp130 antibodies. J Clin Invest. 1995 Sep;96(3):1319–1327. doi: 10.1172/JCI118167. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Noel J. C., Hermans P., Andre J., Fayt I., Simonart T. h., Verhest A., Haot J., Burny A. Herpesvirus-like DNA sequences and Kaposi's sarcoma: relationship with epidemiology, clinical spectrum, and histologic features. Cancer. 1996 May 15;77(10):2132–2136. doi: 10.1002/(SICI)1097-0142(19960515)77:10<2132::AID-CNCR26>3.0.CO;2-V. [DOI] [PubMed] [Google Scholar]
  29. Radka S. F., Nakamura S., Sakurada S., Salahuddin S. Z. Correlation of oncostatin M secretion by human retrovirus-infected cells with potent growth stimulation of cultured spindle cells from AIDS-Kaposi's sarcoma. J Immunol. 1993 Jun 1;150(11):5195–5201. [PubMed] [Google Scholar]
  30. Scala G., Ruocco M. R., Ambrosino C., Mallardo M., Giordano V., Baldassarre F., Dragonetti E., Quinto I., Venuta S. The expression of the interleukin 6 gene is induced by the human immunodeficiency virus 1 TAT protein. J Exp Med. 1994 Mar 1;179(3):961–971. doi: 10.1084/jem.179.3.961. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Staden R. Finding protein coding regions in genomic sequences. Methods Enzymol. 1990;183:163–180. doi: 10.1016/0076-6879(90)83012-x. [DOI] [PubMed] [Google Scholar]
  32. Stürzl M., Brandstetter H., Zietz C., Eisenburg B., Raivich G., Gearing D. P., Brockmeyer N. H., Hofschneider P. H. Identification of interleukin-1 and platelet-derived growth factor-B as major mitogens for the spindle cells of Kaposi's sarcoma: a combined in vitro and in vivo analysis. Oncogene. 1995 May 18;10(10):2007–2016. [PubMed] [Google Scholar]
  33. Trimble J. J., Murthy S. C., Bakker A., Grassmann R., Desrosiers R. C. A gene for dihydrofolate reductase in a herpesvirus. Science. 1988 Mar 4;239(4844):1145–1147. doi: 10.1126/science.2830673. [DOI] [PubMed] [Google Scholar]
  34. Yang J., Hagan M. K., Offermann M. K. Induction of IL-6 gene expression in Kaposi's sarcoma cells. J Immunol. 1994 Jan 15;152(2):943–955. [PubMed] [Google Scholar]
  35. de Lellis L., Fabris M., Cassai E., Corallini A., Giraldo G., Feo C., Monini P. Herpesvirus-like DNA sequences in non-AIDS Kaposi's sarcoma. J Infect Dis. 1995 Dec;172(6):1605–1607. doi: 10.1093/infdis/172.6.1605. [DOI] [PubMed] [Google Scholar]
  36. van Dam M., Müllberg J., Schooltink H., Stoyan T., Brakenhoff J. P., Graeve L., Heinrich P. C., Rose-John S. Structure-function analysis of interleukin-6 utilizing human/murine chimeric molecules. Involvement of two separate domains in receptor binding. J Biol Chem. 1993 Jul 15;268(20):15285–15290. [PubMed] [Google Scholar]

Articles from Journal of Virology are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES