Skip to main content
Journal of Virology logoLink to Journal of Virology
. 1996 Feb;70(2):1143–1153. doi: 10.1128/jvi.70.2.1143-1153.1996

A novel interleukin-12 p40-related protein induced by latent Epstein-Barr virus infection in B lymphocytes.

O Devergne 1, M Hummel 1, H Koeppen 1, M M Le Beau 1, E C Nathanson 1, E Kieff 1, M Birkenbach 1
PMCID: PMC189923  PMID: 8551575

Abstract

We have isolated a cDNA encoding a novel hematopoietin receptor family member related to the p40 subunit of interleukin-12 and to the ciliary neurotrophic factor receptor, whose expression is induced in B lymphocytes by Epstein-Barr virus (EBV) infection. This gene, which we have designated EBV-induced gene 3 (EBI3), encodes a 34-kDa glycoprotein which lacks a membrane-anchoring motif and is secreted. Despite the absence of a membrane-anchoring motif and of cysteines likely to mediate covalent linkage to an integral membrane protein, EBI3 is also present on the plasma membrane of EBV-transformed B lymphocytes and of transfected cells. Most newly synthesized EBI3 is retained in the endoplasmic reticulum in an endoglycosidase H-sensitive form associated with the molecular chaperone calnexin and with a novel 60-kDa protein. EBI3 is expressed in vivo by scattered cells in interfollicular zones of tonsil tissue, by cells associated with sinusoids in perifollicular areas of spleen tissue, and at very high levels by placental syncytiotrophoblasts. EBI3 expression in vitro is induced in EBV-negative cell lines by expression of the EBV latent infection membrane protein-1 and in peripheral blood mononuclear cells by pokeweed mitogen stimulation. EBI3 maps to chromosome 19p13.2/3, near genes encoding the erythropoietin receptor and the cytokine receptor-associated kinase, Tyk2. EBI3 synthesis by trophoblasts and by EBV-transformed cells and similarities to interleukin-12 p40 are compatible with a role for EBI3 in regulating cell-mediated immune responses.

Full Text

The Full Text of this article is available as a PDF (834.5 KB).

Selected References

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

  1. 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]
  2. Baumann M. A., Paul C. C. Interleukin-5 is an autocrine growth factor for Epstein-Barr virus-transformed B lymphocytes. Blood. 1992 Apr 1;79(7):1763–1767. [PubMed] [Google Scholar]
  3. Bazan J. F. Structural design and molecular evolution of a cytokine receptor superfamily. Proc Natl Acad Sci U S A. 1990 Sep;87(18):6934–6938. doi: 10.1073/pnas.87.18.6934. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bergeron J. J., Brenner M. B., Thomas D. Y., Williams D. B. Calnexin: a membrane-bound chaperone of the endoplasmic reticulum. Trends Biochem Sci. 1994 Mar;19(3):124–128. doi: 10.1016/0968-0004(94)90205-4. [DOI] [PubMed] [Google Scholar]
  5. Birkenbach M., Josefsen K., Yalamanchili R., Lenoir G., Kieff E. Epstein-Barr virus-induced genes: first lymphocyte-specific G protein-coupled peptide receptors. J Virol. 1993 Apr;67(4):2209–2220. doi: 10.1128/jvi.67.4.2209-2220.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Birkenbach M., Liebowitz D., Wang F., Sample J., Kieff E. Epstein-Barr virus latent infection membrane protein increases vimentin expression in human B-cell lines. J Virol. 1989 Sep;63(9):4079–4084. doi: 10.1128/jvi.63.9.4079-4084.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Blazar B. A., Sutton L. M., Strome M. Self-stimulating growth factor production by B-cell lines derived from Burkitt's lymphomas and other lines transformed in vitro by Epstein-Barr virus. Cancer Res. 1983 Oct;43(10):4562–4568. [PubMed] [Google Scholar]
  8. Boyd A. W., Anderson K. C., Freedman A. S., Fisher D. C., Slaughenhoupt B., Schlossman S. F., Nadler L. M. Studies of in vitro activation and differentiation of human B lymphocytes. I. Phenotypic and functional characterization of the B cell population responding to anti-Ig antibody. J Immunol. 1985 Mar;134(3):1516–1523. [PubMed] [Google Scholar]
  9. Browning J. L., Ngam-ek A., Lawton P., DeMarinis J., Tizard R., Chow E. P., Hession C., O'Brine-Greco B., Foley S. F., Ware C. F. Lymphotoxin beta, a novel member of the TNF family that forms a heteromeric complex with lymphotoxin on the cell surface. Cell. 1993 Mar 26;72(6):847–856. doi: 10.1016/0092-8674(93)90574-a. [DOI] [PubMed] [Google Scholar]
  10. Buck J., Hämmerling U., Hoffmann M. K., Levi E., Welte K. Purification and biochemical characterization of a human autocrine growth factor produced by Epstein-Barr virus-transformed B cells. J Immunol. 1987 May 1;138(9):2923–2928. [PubMed] [Google Scholar]
  11. Burdin N., Péronne C., Banchereau J., Rousset F. Epstein-Barr virus transformation induces B lymphocytes to produce human interleukin 10. J Exp Med. 1993 Feb 1;177(2):295–304. doi: 10.1084/jem.177.2.295. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Calender A., Billaud M., Aubry J. P., Banchereau J., Vuillaume M., Lenoir G. M. Epstein-Barr virus (EBV) induces expression of B-cell activation markers on in vitro infection of EBV-negative B-lymphoma cells. Proc Natl Acad Sci U S A. 1987 Nov;84(22):8060–8064. doi: 10.1073/pnas.84.22.8060. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Calender A., Cordier M., Billaud M., Lenoir G. M. Modulation of cellular gene expression in B lymphoma cells following in vitro infection by Epstein-Barr virus (EBV). Int J Cancer. 1990 Oct 15;46(4):658–663. doi: 10.1002/ijc.2910460418. [DOI] [PubMed] [Google Scholar]
  14. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  15. Corless C. L., Matzuk M. M., Ramabhadran T. V., Krichevsky A., Boime I. Gonadotropin beta subunits determine the rate of assembly and the oligosaccharide processing of hormone dimer in transfected cells. J Cell Biol. 1987 May;104(5):1173–1181. doi: 10.1083/jcb.104.5.1173. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Cosman D. The hematopoietin receptor superfamily. Cytokine. 1993 Mar;5(2):95–106. doi: 10.1016/1043-4666(93)90047-9. [DOI] [PubMed] [Google Scholar]
  17. D'Andrea A., Aste-Amezaga M., Valiante N. M., Ma X., Kubin M., Trinchieri G. Interleukin 10 (IL-10) inhibits human lymphocyte interferon gamma-production by suppressing natural killer cell stimulatory factor/IL-12 synthesis in accessory cells. J Exp Med. 1993 Sep 1;178(3):1041–1048. doi: 10.1084/jem.178.3.1041. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. D'Andrea A., Rengaraju M., Valiante N. M., Chehimi J., Kubin M., Aste M., Chan S. H., Kobayashi M., Young D., Nickbarg E. Production of natural killer cell stimulatory factor (interleukin 12) by peripheral blood mononuclear cells. J Exp Med. 1992 Nov 1;176(5):1387–1398. doi: 10.1084/jem.176.5.1387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. David V., Hochstenbach F., Rajagopalan S., Brenner M. B. Interaction with newly synthesized and retained proteins in the endoplasmic reticulum suggests a chaperone function for human integral membrane protein IP90 (calnexin). J Biol Chem. 1993 May 5;268(13):9585–9592. [PubMed] [Google Scholar]
  20. Davis S., Aldrich T. H., Valenzuela D. M., Wong V. V., Furth M. E., Squinto S. P., Yancopoulos G. D. The receptor for ciliary neurotrophic factor. Science. 1991 Jul 5;253(5015):59–63. doi: 10.1126/science.1648265. [DOI] [PubMed] [Google Scholar]
  21. Dezelee S., Bras F., Contamine D., Lopez-Ferber M., Segretain D., Teninges D. Molecular analysis of ref(2)P, a Drosophila gene implicated in sigma rhabdovirus multiplication and necessary for male fertility. EMBO J. 1989 Nov;8(11):3437–3446. doi: 10.1002/j.1460-2075.1989.tb08508.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Ehlin-Henriksson B., Manneborg-Sandlund A., Klein G. Expression of B-cell-specific markers in different Burkitt lymphoma subgroups. Int J Cancer. 1987 Feb 15;39(2):211–218. doi: 10.1002/ijc.2910390215. [DOI] [PubMed] [Google Scholar]
  23. Englund P. T. The structure and biosynthesis of glycosyl phosphatidylinositol protein anchors. Annu Rev Biochem. 1993;62:121–138. doi: 10.1146/annurev.bi.62.070193.001005. [DOI] [PubMed] [Google Scholar]
  24. Estrov Z., Kurzrock R., Pocsik E., Pathak S., Kantarjian H. M., Zipf T. F., Harris D., Talpaz M., Aggarwal B. B. Lymphotoxin is an autocrine growth factor for Epstein-Barr virus-infected B cell lines. J Exp Med. 1993 Mar 1;177(3):763–774. doi: 10.1084/jem.177.3.763. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Fernandez-Botran R. Soluble cytokine receptors: their role in immunoregulation. FASEB J. 1991 Aug;5(11):2567–2574. doi: 10.1096/fasebj.5.11.1868981. [DOI] [PubMed] [Google Scholar]
  26. Firmbach-Kraft I., Byers M., Shows T., Dalla-Favera R., Krolewski J. J. tyk2, prototype of a novel class of non-receptor tyrosine kinase genes. Oncogene. 1990 Sep;5(9):1329–1336. [PubMed] [Google Scholar]
  27. Galvin K., Krishna S., Ponchel F., Frohlich M., Cummings D. E., Carlson R., Wands J. R., Isselbacher K. J., Pillai S., Ozturk M. The major histocompatibility complex class I antigen-binding protein p88 is the product of the calnexin gene. Proc Natl Acad Sci U S A. 1992 Sep 15;89(18):8452–8456. doi: 10.1073/pnas.89.18.8452. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Gibbons D. L., Rowe M., Cope A. P., Feldmann M., Brennan F. M. Lymphotoxin acts as an autocrine growth factor for Epstein-Barr virus-transformed B cells and differentiated Burkitt lymphoma cell lines. Eur J Immunol. 1994 Aug;24(8):1879–1885. doi: 10.1002/eji.1830240825. [DOI] [PubMed] [Google Scholar]
  29. Gregory C. D., Rowe M., Rickinson A. B. Different Epstein-Barr virus-B cell interactions in phenotypically distinct clones of a Burkitt's lymphoma cell line. J Gen Virol. 1990 Jul;71(Pt 7):1481–1495. doi: 10.1099/0022-1317-71-7-1481. [DOI] [PubMed] [Google Scholar]
  30. Gubler U., Chua A. O., Schoenhaut D. S., Dwyer C. M., McComas W., Motyka R., Nabavi N., Wolitzky A. G., Quinn P. M., Familletti P. C. Coexpression of two distinct genes is required to generate secreted bioactive cytotoxic lymphocyte maturation factor. Proc Natl Acad Sci U S A. 1991 May 15;88(10):4143–4147. doi: 10.1073/pnas.88.10.4143. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Hammond C., Helenius A. Folding of VSV G protein: sequential interaction with BiP and calnexin. Science. 1994 Oct 21;266(5184):456–458. doi: 10.1126/science.7939687. [DOI] [PubMed] [Google Scholar]
  32. Hasegawa H., Utsunomiya Y., Yasukawa M., Yanagisawa K., Fujita S. Induction of G protein-coupled peptide receptor EBI 1 by human herpesvirus 6 and 7 infection in CD4+ T cells. J Virol. 1994 Aug;68(8):5326–5329. doi: 10.1128/jvi.68.8.5326-5329.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Henle G., Henle W., Diehl V. Relation of Burkitt's tumor-associated herpes-ytpe virus to infectious mononucleosis. Proc Natl Acad Sci U S A. 1968 Jan;59(1):94–101. doi: 10.1073/pnas.59.1.94. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Herbst H., Dallenbach F., Hummel M., Niedobitek G., Pileri S., Müller-Lantzsch N., Stein H. Epstein-Barr virus latent membrane protein expression in Hodgkin and Reed-Sternberg cells. Proc Natl Acad Sci U S A. 1991 Jun 1;88(11):4766–4770. doi: 10.1073/pnas.88.11.4766. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Higgins D. G., Sharp P. M. CLUSTAL: a package for performing multiple sequence alignment on a microcomputer. Gene. 1988 Dec 15;73(1):237–244. doi: 10.1016/0378-1119(88)90330-7. [DOI] [PubMed] [Google Scholar]
  36. Hilton D. J., Watowich S. S., Murray P. J., Lodish H. F. Increased cell surface expression and enhanced folding in the endoplasmic reticulum of a mutant erythropoietin receptor. Proc Natl Acad Sci U S A. 1995 Jan 3;92(1):190–194. doi: 10.1073/pnas.92.1.190. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Hochstenbach F., David V., Watkins S., Brenner M. B. Endoplasmic reticulum resident protein of 90 kilodaltons associates with the T- and B-cell antigen receptors and major histocompatibility complex antigens during their assembly. Proc Natl Acad Sci U S A. 1992 May 15;89(10):4734–4738. doi: 10.1073/pnas.89.10.4734. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Kozak M. Structural features in eukaryotic mRNAs that modulate the initiation of translation. J Biol Chem. 1991 Oct 25;266(30):19867–19870. [PubMed] [Google Scholar]
  39. Lenoir G. M., Vuillaume M., Bonnardel C. The use of lymphomatous and lymphoblastoid cell lines in the study of Burkitt's lymphoma. IARC Sci Publ. 1985;(60):309–318. [PubMed] [Google Scholar]
  40. Lin H., Mosmann T. R., Guilbert L., Tuntipopipat S., Wegmann T. G. Synthesis of T helper 2-type cytokines at the maternal-fetal interface. J Immunol. 1993 Nov 1;151(9):4562–4573. [PubMed] [Google Scholar]
  41. Ling P., Gately M. K., Gubler U., Stern A. S., Lin P., Hollfelder K., Su C., Pan Y. C., Hakimi J. Human IL-12 p40 homodimer binds to the IL-12 receptor but does not mediate biologic activity. J Immunol. 1995 Jan 1;154(1):116–127. [PubMed] [Google Scholar]
  42. Moore K. W., Vieira P., Fiorentino D. F., Trounstine M. L., Khan T. A., Mosmann T. R. Homology of cytokine synthesis inhibitory factor (IL-10) to the Epstein-Barr virus gene BCRFI. Science. 1990 Jun 8;248(4960):1230–1234. doi: 10.1126/science.2161559. [DOI] [PubMed] [Google Scholar]
  43. Mosialos G., Birkenbach M., Yalamanchili R., VanArsdale T., Ware C., Kieff E. The Epstein-Barr virus transforming protein LMP1 engages signaling proteins for the tumor necrosis factor receptor family. Cell. 1995 Feb 10;80(3):389–399. doi: 10.1016/0092-8674(95)90489-1. [DOI] [PubMed] [Google Scholar]
  44. Mosialos G., Yamashiro S., Baughman R. W., Matsudaira P., Vara L., Matsumura F., Kieff E., Birkenbach M. Epstein-Barr virus infection induces expression in B lymphocytes of a novel gene encoding an evolutionarily conserved 55-kilodalton actin-bundling protein. J Virol. 1994 Nov;68(11):7320–7328. doi: 10.1128/jvi.68.11.7320-7328.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Nilsson K., Klein G., Henle W., Henle G. The establishment of lymphoblastoid lines from adult and fetal human lymphoid tissue and its dependence on EBV. Int J Cancer. 1971 Nov 15;8(3):443–450. doi: 10.1002/ijc.2910080312. [DOI] [PubMed] [Google Scholar]
  46. Nilsson K., Klein G. Phenotypic and cytogenetic characteristics of human B-lymphoid cell lines and their relevance for the etiology of Burkitt's lymphoma. Adv Cancer Res. 1982;37:319–380. doi: 10.1016/s0065-230x(08)60886-6. [DOI] [PubMed] [Google Scholar]
  47. Ou W. J., Cameron P. H., Thomas D. Y., Bergeron J. J. Association of folding intermediates of glycoproteins with calnexin during protein maturation. Nature. 1993 Aug 26;364(6440):771–776. doi: 10.1038/364771a0. [DOI] [PubMed] [Google Scholar]
  48. Rajagopalan S., Xu Y., Brenner M. B. Retention of unassembled components of integral membrane proteins by calnexin. Science. 1994 Jan 21;263(5145):387–390. doi: 10.1126/science.8278814. [DOI] [PubMed] [Google Scholar]
  49. Rowe M., Rooney C. M., Edwards C. F., Lenoir G. M., Rickinson A. B. Epstein-Barr virus status and tumour cell phenotype in sporadic Burkitt's lymphoma. Int J Cancer. 1986 Mar 15;37(3):367–373. doi: 10.1002/ijc.2910370307. [DOI] [PubMed] [Google Scholar]
  50. Rowley J. D., Diaz M. O., Espinosa R., 3rd, Patel Y. D., van Melle E., Ziemin S., Taillon-Miller P., Lichter P., Evans G. A., Kersey J. H. Mapping chromosome band 11q23 in human acute leukemia with biotinylated probes: identification of 11q23 translocation breakpoints with a yeast artificial chromosome. Proc Natl Acad Sci U S A. 1990 Dec;87(23):9358–9362. doi: 10.1073/pnas.87.23.9358. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Sakano S., Iwama A., Inazawa J., Ariyama T., Ohno M., Suda T. Molecular cloning of a novel non-receptor tyrosine kinase, HYL (hematopoietic consensus tyrosine-lacking kinase). Oncogene. 1994 Apr;9(4):1155–1161. [PubMed] [Google Scholar]
  52. Stahl N., Boulton T. G., Farruggella T., Ip N. Y., Davis S., Witthuhn B. A., Quelle F. W., Silvennoinen O., Barbieri G., Pellegrini S. Association and activation of Jak-Tyk kinases by CNTF-LIF-OSM-IL-6 beta receptor components. Science. 1994 Jan 7;263(5143):92–95. doi: 10.1126/science.8272873. [DOI] [PubMed] [Google Scholar]
  53. Suzuki T., Sanders S. K., Butler J. L., Gartland G. L., Komiyama K., Cooper M. D. Identification of an early activation antigen (Bac-1) on human B cells. J Immunol. 1986 Aug 15;137(4):1208–1213. [PubMed] [Google Scholar]
  54. Swendeman S., Thorley-Lawson D. A. The activation antigen BLAST-2, when shed, is an autocrine BCGF for normal and transformed B cells. EMBO J. 1987 Jun;6(6):1637–1642. doi: 10.1002/j.1460-2075.1987.tb02412.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Thorley-Lawson D. A., Mann K. P. Early events in Epstein-Barr virus infection provide a model for B cell activation. J Exp Med. 1985 Jul 1;162(1):45–59. doi: 10.1084/jem.162.1.45. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Thorley-Lawson D. A., Nadler L. M., Bhan A. K., Schooley R. T. BLAST-2 [EBVCS], an early cell surface marker of human B cell activation, is superinduced by Epstein Barr virus. J Immunol. 1985 May;134(5):3007–3012. [PubMed] [Google Scholar]
  57. Tosato G., Tanner J., Jones K. D., Revel M., Pike S. E. Identification of interleukin-6 as an autocrine growth factor for Epstein-Barr virus-immortalized B cells. J Virol. 1990 Jun;64(6):3033–3041. doi: 10.1128/jvi.64.6.3033-3041.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Trinchieri G. Interleukin-12 and its role in the generation of TH1 cells. Immunol Today. 1993 Jul;14(7):335–338. doi: 10.1016/0167-5699(93)90230-I. [DOI] [PubMed] [Google Scholar]
  59. Wang F., Gregory C., Sample C., Rowe M., Liebowitz D., Murray R., Rickinson A., Kieff E. Epstein-Barr virus latent membrane protein (LMP1) and nuclear proteins 2 and 3C are effectors of phenotypic changes in B lymphocytes: EBNA-2 and LMP1 cooperatively induce CD23. J Virol. 1990 May;64(5):2309–2318. doi: 10.1128/jvi.64.5.2309-2318.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Wegmann T. G., Lin H., Guilbert L., Mosmann T. R. Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenon? Immunol Today. 1993 Jul;14(7):353–356. doi: 10.1016/0167-5699(93)90235-D. [DOI] [PubMed] [Google Scholar]
  61. Wendel-Hansen V., Rivière M., Uno M., Jansson I., Szpirer J., Islam M. Q., Levan G., Klein G., Yodoi J., Rosén A. The gene encoding CD23 leukocyte antigen (FCE2) is located on human chromosome 19. Somat Cell Mol Genet. 1990 May;16(3):283–286. doi: 10.1007/BF01233364. [DOI] [PubMed] [Google Scholar]
  62. Winkelmann J. C., Penny L. A., Deaven L. L., Forget B. G., Jenkins R. B. The gene for the human erythropoietin receptor: analysis of the coding sequence and assignment to chromosome 19p. Blood. 1990 Jul 1;76(1):24–30. [PubMed] [Google Scholar]
  63. Wolf S. F., Temple P. A., Kobayashi M., Young D., Dicig M., Lowe L., Dzialo R., Fitz L., Ferenz C., Hewick R. M. Cloning of cDNA for natural killer cell stimulatory factor, a heterodimeric cytokine with multiple biologic effects on T and natural killer cells. J Immunol. 1991 May 1;146(9):3074–3081. [PubMed] [Google Scholar]

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

RESOURCES