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Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1993 Jul 1;90(13):6330–6334. doi: 10.1073/pnas.90.13.6330

Identification of a cDNA for a human high-molecular-weight B-cell growth factor.

J L Ambrus Jr 1, J Pippin 1, A Joseph 1, C Xu 1, D Blumenthal 1, A Tamayo 1, K Claypool 1, D McCourt 1, A Srikiatchatochorn 1, R J Ford 1
PMCID: PMC46922  PMID: 8327514

Abstract

Proliferation is necessary for many of the phenotypic changes that occur during B-cell maturation. Further differentiation of mature B cells into plasma cells or memory B cells requires additional rounds of proliferation. In this manuscript, we describe a cDNA for a human B-cell growth factor we call high-molecular-weight B-cell growth factor (HMW-BCGF). Purified HMW-BCGF has been shown to induce B-cell proliferation, inhibit immunoglobulin secretion, and selectively expand certain B-cell subpopulations. Studies using antibodies to HMW-BCGF and its receptor have suggested that HMW-BCGF, while produced by T cells and some malignant B cells, acts predominantly on normal and malignant B cells. The HMW-BCGF cDNA was identified by expression cloning using a monoclonal antibody and polyclonal antisera to HMW-BCGF. Protein produced from the cDNA induced B-cell proliferation, inhibited immunoglobulin secretion, and was recognized in immunoblots by anti-HMW-BCGF antibodies. The amino acid sequence of HMW-BCGF deduced from the cDNA predicts a secreted protein of 53 kDa with three potential N-linked glycosylation sites. The identification of this cDNA will allow further studies examining physiologic roles of this cytokine. We propose to call it interleukin 14.

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  1. Alt F. W., Blackwell T. K., Yancopoulos G. D. Development of the primary antibody repertoire. Science. 1987 Nov 20;238(4830):1079–1087. doi: 10.1126/science.3317825. [DOI] [PubMed] [Google Scholar]
  2. Ambrus J. L., Jr, Chesky L., Chused T., Young K. R., Jr, McFarland P., August A., Brown E. J. Intracellular signaling events associated with the induction of proliferation of normal human B lymphocytes by two different antigenically related human B cell growth factors (high molecular weight B cell growth factor (HMW-BCGF) and the complement factor Bb). J Biol Chem. 1991 Feb 25;266(6):3702–3708. [PubMed] [Google Scholar]
  3. Ambrus J. L., Jr, Chesky L., McFarland P., Young K. R., Jr, Mostowski H., August A., Chused T. M. Induction of proliferation by high molecular weight B cell growth factor or low molecular weight B cell growth factor is associated with increases in intracellular calcium in different subpopulations of human B lymphocytes. Cell Immunol. 1991 May;134(2):314–324. doi: 10.1016/0008-8749(91)90305-u. [DOI] [PubMed] [Google Scholar]
  4. Ambrus J. L., Jr, Chesky L., Stephany D., McFarland P., Mostowski H., Fauci A. S. Functional studies examining the subpopulation of human B lymphocytes responding to high molecular weight B cell growth factor. J Immunol. 1990 Dec 15;145(12):3949–3955. [PubMed] [Google Scholar]
  5. Ambrus J. L., Jr, Fauci A. S. Human B lymphoma cell line producing B cell growth factor. J Clin Invest. 1985 Feb;75(2):732–739. doi: 10.1172/JCI111754. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Ambrus J. L., Jr, Haneiwich S., Chesky L., McFarland P., Peters M. G., Engler R. J. Abnormal response to a human B cell growth factor in patients with common variable immunodeficiency (CVI). J Allergy Clin Immunol. 1991 Jun;87(6):1138–1149. doi: 10.1016/0091-6749(91)92160-3. [DOI] [PubMed] [Google Scholar]
  7. Ambrus J. L., Jr, Jurgensen C. H., Bowen D. L., Tomita S., Nakagawa T., Nakagawa N., Goldstein H., Witzel N. L., Mostowski H. S., Fauci A. S. The activation, proliferation, and differentiation of human B lymphocytes. Adv Exp Med Biol. 1987;213:163–175. doi: 10.1007/978-1-4684-5323-2_16. [DOI] [PubMed] [Google Scholar]
  8. Ambrus J. L., Jr, Jurgensen C. H., Brown E. J., Fauci A. S. Purification to homogeneity of a high molecular weight human B cell growth factor; demonstration of specific binding to activated B cells; and development of a monoclonal antibody to the factor. J Exp Med. 1985 Oct 1;162(4):1319–1335. doi: 10.1084/jem.162.4.1319. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Ambrus J. L., Jr, Jurgensen C. H., Brown E. J., McFarland P., Fauci A. S. Identification of a receptor for high molecular weight human B cell growth factor. J Immunol. 1988 Aug 1;141(3):861–869. [PubMed] [Google Scholar]
  10. Andrews D. W., Young J. C., Mirels L. F., Czarnota G. J. The role of the N region in signal sequence and signal-anchor function. J Biol Chem. 1992 Apr 15;267(11):7761–7769. [PubMed] [Google Scholar]
  11. Azuma C., Tanabe T., Konishi M., Kinashi T., Noma T., Matsuda F., Yaoita Y., Takatsu K., Hammarström L., Smith C. I. Cloning of cDNA for human T-cell replacing factor (interleukin-5) and comparison with the murine homologue. Nucleic Acids Res. 1986 Nov 25;14(22):9149–9158. doi: 10.1093/nar/14.22.9149. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Banchereau J., Rousset F. Functions of interleukin-4 on human B lymphocytes. Immunol Res. 1991;10(3-4):423–427. doi: 10.1007/BF02919735. [DOI] [PubMed] [Google Scholar]
  13. Banchereau J., de Paoli P., Vallé A., Garcia E., Rousset F. Long-term human B cell lines dependent on interleukin-4 and antibody to CD40. Science. 1991 Jan 4;251(4989):70–72. doi: 10.1126/science.1702555. [DOI] [PubMed] [Google Scholar]
  14. Callard R. E., Smith S. H., Scott K. E. The role of interleukin 4 in specific antibody responses by human B cells. Int Immunol. 1991 Feb;3(2):157–163. doi: 10.1093/intimm/3.2.157. [DOI] [PubMed] [Google Scholar]
  15. Carel J. C., Frazier B., Ley T. J., Holers V. M. Analysis of epitope expression and the functional repertoire of recombinant complement receptor 2 (CR2/CD21) in mouse and human cells. J Immunol. 1989 Aug 1;143(3):923–930. [PubMed] [Google Scholar]
  16. Claassen J. L., Levine A. D., Buckley R. H. Recombinant human IL-4 induces IgE and IgG synthesis by normal and atopic donor mononuclear cells. Similar dose response, time course, requirement for T cells, and effect of pokeweed mitogen. J Immunol. 1990 Mar 15;144(6):2123–2130. [PubMed] [Google Scholar]
  17. Clark E. A., Shu G. L., Lüscher B., Draves K. E., Banchereau J., Ledbetter J. A., Valentine M. A. Activation of human B cells. Comparison of the signal transduced by IL-4 to four different competence signals. J Immunol. 1989 Dec 15;143(12):3873–3880. [PubMed] [Google Scholar]
  18. Clayberger C., Luna-Fineman S., Lee J. E., Pillai A., Campbell M., Levy R., Krensky A. M. Interleukin 3 is a growth factor for human follicular B cell lymphoma. J Exp Med. 1992 Feb 1;175(2):371–376. doi: 10.1084/jem.175.2.371. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. DeFranco A. L. Molecular aspects of B-lymphocyte activation. Annu Rev Cell Biol. 1987;3:143–178. doi: 10.1146/annurev.cb.03.110187.001043. [DOI] [PubMed] [Google Scholar]
  20. Defrance T., Aubry J. P., Vanbervliet B., Banchereau J. Human interferon-gamma acts as a B cell growth factor in the anti-IgM antibody co-stimulatory assay but has no direct B cell differentiation activity. J Immunol. 1986 Dec 15;137(12):3861–3867. [PubMed] [Google Scholar]
  21. Defrance T., Vanbervliet B., Aubry J. P., Takebe Y., Arai N., Miyajima A., Yokota T., Lee F., Arai K., de Vries J. E. B cell growth-promoting activity of recombinant human interleukin 4. J Immunol. 1987 Aug 15;139(4):1135–1141. [PubMed] [Google Scholar]
  22. Defrance T., Vanbervliet B., Pène J., Banchereau J. Human recombinant IL-4 induces activated B lymphocytes to produce IgG and IgM. J Immunol. 1988 Sep 15;141(6):2000–2005. [PubMed] [Google Scholar]
  23. Del Prete G., Maggi E., Parronchi P., Chrétien I., Tiri A., Macchia D., Ricci M., Banchereau J., De Vries J., Romagnani S. IL-4 is an essential factor for the IgE synthesis induced in vitro by human T cell clones and their supernatants. J Immunol. 1988 Jun 15;140(12):4193–4198. [PubMed] [Google Scholar]
  24. Dunnick W., Wilson M., Stavnezer J. Mutations, duplication, and deletion of recombined switch regions suggest a role for DNA replication in the immunoglobulin heavy-chain switch. Mol Cell Biol. 1989 May;9(5):1850–1856. doi: 10.1128/mcb.9.5.1850. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Finney M., Guy G. R., Michell R. H., Gordon J., Dugas B., Rigley K. P., Callard R. E. Interleukin 4 activates human B lymphocytes via transient inositol lipid hydrolysis and delayed cyclic adenosine monophosphate generation. Eur J Immunol. 1990 Jan;20(1):151–156. doi: 10.1002/eji.1830200122. [DOI] [PubMed] [Google Scholar]
  26. Forni L., Björklund M., Coutinho A. Membrane expression of IgG but not maturation to secretion requires DNA replication. J Mol Cell Immunol. 1988;4(2):59–70. [PubMed] [Google Scholar]
  27. Gimble J. M., Pietrangeli C., Henley A., Dorheim M. A., Silver J., Namen A., Takeichi M., Goridis C., Kincade P. W. Characterization of murine bone marrow and spleen-derived stromal cells: analysis of leukocyte marker and growth factor mRNA transcript levels. Blood. 1989 Jul;74(1):303–311. [PubMed] [Google Scholar]
  28. Goldstein H., Ambrus J. L., Jr, Grove J. H., Margolick J. B., Fauci A. S. Functional and biochemical characterization of B-cell differentiation factor (BCDF) produced by an HTLV-I-transformed human T-cell clone and demonstration of specific binding of the factor to a BCDF responsive cell line. Cell Immunol. 1987 Sep;108(2):343–355. doi: 10.1016/0008-8749(87)90218-8. [DOI] [PubMed] [Google Scholar]
  29. Goldstein H., Koerholz D., Chesky L., Fan X. D., Ambrus J. L., Jr Divergent activities of protein kinases in IL-6-induced differentiation of a human B cell line. J Immunol. 1990 Aug 1;145(3):952–961. [PubMed] [Google Scholar]
  30. Harada H., Shioiri-Nakano K., Mayumi M., Kawai T. Distinction of two subtypes of human leukocyte interferon (IFN-alpha) on B cell activation. B cell proliferation by two subtypes of IFN-alpha. J Immunol. 1983 Jul;131(1):238–243. [PubMed] [Google Scholar]
  31. Jelinek D. F., Lipsky P. E. Enhancement of human B cell proliferation and differentiation by tumor necrosis factor-alpha and interleukin 1. J Immunol. 1987 Nov 1;139(9):2970–2976. [PubMed] [Google Scholar]
  32. Jelinek D. F., Lipsky P. E. Regulation of human B lymphocyte activation, proliferation, and differentiation. Adv Immunol. 1987;40:1–59. doi: 10.1016/s0065-2776(08)60237-0. [DOI] [PubMed] [Google Scholar]
  33. Kehrl J. H., Miller A., Fauci A. S. Effect of tumor necrosis factor alpha on mitogen-activated human B cells. J Exp Med. 1987 Sep 1;166(3):786–791. doi: 10.1084/jem.166.3.786. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Kehrl J. H., Muraguchi A., Butler J. L., Falkoff R. J., Fauci A. S. Human B cell activation, proliferation and differentiation. Immunol Rev. 1984 Apr;78:75–96. doi: 10.1111/j.1600-065x.1984.tb00477.x. [DOI] [PubMed] [Google Scholar]
  35. 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]
  36. Kühn R., Rajewsky K., Müller W. Generation and analysis of interleukin-4 deficient mice. Science. 1991 Nov 1;254(5032):707–710. doi: 10.1126/science.1948049. [DOI] [PubMed] [Google Scholar]
  37. Llorente L., Mitjavila F., Crevon M. C., Galanaud P. Dual effects of interleukin 4 on antigen-activated human B cells: induction of proliferation and inhibition of interleukin 2-dependent differentiation. Eur J Immunol. 1990 Sep;20(9):1887–1892. doi: 10.1002/eji.1830200903. [DOI] [PubMed] [Google Scholar]
  38. MacLennan I. C., Liu Y. J., Johnson G. D. Maturation and dispersal of B-cell clones during T cell-dependent antibody responses. Immunol Rev. 1992 Apr;126:143–161. doi: 10.1111/j.1600-065x.1992.tb00635.x. [DOI] [PubMed] [Google Scholar]
  39. McKenzie D. T., Filutowicz H. I., Swain S. L., Dutton R. W. Purification and partial sequence analysis of murine B cell growth factor II (interleukin 5). J Immunol. 1987 Oct 15;139(8):2661–2668. [PubMed] [Google Scholar]
  40. Mehta S. R., Conrad D., Sandler R., Morgan J., Montagna R., Maizel A. L. Purification of human B cell growth factor. J Immunol. 1985 Nov;135(5):3298–3302. [PubMed] [Google Scholar]
  41. Morrissey P. J., Conlon P., Charrier K., Braddy S., Alpert A., Williams D., Namen A. E., Mochizuki D. Administration of IL-7 to normal mice stimulates B-lymphopoiesis and peripheral lymphadenopathy. J Immunol. 1991 Jul 15;147(2):561–568. [PubMed] [Google Scholar]
  42. Muraguchi A., Kehrl J. H., Longo D. L., Volkman D. J., Smith K. A., Fauci A. S. Interleukin 2 receptors on human B cells. Implications for the role of interleukin 2 in human B cell function. J Exp Med. 1985 Jan 1;161(1):181–197. doi: 10.1084/jem.161.1.181. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. O'Garra A., Umland S., De France T., Christiansen J. 'B-cell factors' are pleiotropic. Immunol Today. 1988 Feb;9(2):45–54. doi: 10.1016/0167-5699(88)91259-5. [DOI] [PubMed] [Google Scholar]
  44. Osmond D. G. B cell development in the bone marrow. Semin Immunol. 1990 May;2(3):173–180. [PubMed] [Google Scholar]
  45. Pastorelli G., Roncarolo M. G., Touraine J. L., Rousset F., Pene J., de Vries J. E. Interleukin-4 suppresses immunoglobulin production by peripheral blood lymphocytes of patients with common variable immunodeficiency (CVI) induced by supernatants of T cell clones. Clin Exp Immunol. 1989 Dec;78(3):341–347. [PMC free article] [PubMed] [Google Scholar]
  46. Paul W. E. Interleukin-4: a prototypic immunoregulatory lymphokine. Blood. 1991 May 1;77(9):1859–1870. [PubMed] [Google Scholar]
  47. Paul W. E. Pleiotropy and redundancy: T cell-derived lymphokines in the immune response. Cell. 1989 May 19;57(4):521–524. doi: 10.1016/0092-8674(89)90121-9. [DOI] [PubMed] [Google Scholar]
  48. Peters M. G., Ambrus J. L., Jr, Fauci A. S., Brown E. J. The Bb fragment of complement factor B acts as a B cell growth factor. J Exp Med. 1988 Oct 1;168(4):1225–1235. doi: 10.1084/jem.168.4.1225. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Rousset F., Garcia E., Defrance T., Péronne C., Vezzio N., Hsu D. H., Kastelein R., Moore K. W., Banchereau J. Interleukin 10 is a potent growth and differentiation factor for activated human B lymphocytes. Proc Natl Acad Sci U S A. 1992 Mar 1;89(5):1890–1893. doi: 10.1073/pnas.89.5.1890. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Sanderson C. J., Campbell H. D., Young I. G. Molecular and cellular biology of eosinophil differentiation factor (interleukin-5) and its effects on human and mouse B cells. Immunol Rev. 1988 Feb;102:29–50. doi: 10.1111/j.1600-065x.1988.tb00740.x. [DOI] [PubMed] [Google Scholar]
  51. Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Short J. M., Fernandez J. M., Sorge J. A., Huse W. D. Lambda ZAP: a bacteriophage lambda expression vector with in vivo excision properties. Nucleic Acids Res. 1988 Aug 11;16(15):7583–7600. doi: 10.1093/nar/16.15.7583. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Spriggs M. K., Armitage R. J., Strockbine L., Clifford K. N., Macduff B. M., Sato T. A., Maliszewski C. R., Fanslow W. C. Recombinant human CD40 ligand stimulates B cell proliferation and immunoglobulin E secretion. J Exp Med. 1992 Dec 1;176(6):1543–1550. doi: 10.1084/jem.176.6.1543. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Thomas P. S. Hybridization of denatured RNA and small DNA fragments transferred to nitrocellulose. Proc Natl Acad Sci U S A. 1980 Sep;77(9):5201–5205. doi: 10.1073/pnas.77.9.5201. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Uckun F. M., Dibirdik I., Smith R., Tuel-Ahlgren L., Chandan-Langlie M., Schieven G. L., Waddick K. G., Hanson M., Ledbetter J. A. Interleukin 7 receptor ligation stimulates tyrosine phosphorylation, inositol phospholipid turnover, and clonal proliferation of human B-cell precursors. Proc Natl Acad Sci U S A. 1991 May 1;88(9):3589–3593. doi: 10.1073/pnas.88.9.3589. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Uckun F. M., Fauci A. S., Chandan-Langlie M., Myers D. E., Ambrus J. L. Detection and characterization of human high molecular weight B cell growth factor receptors on leukemic B cells in chronic lymphocytic leukemia. J Clin Invest. 1989 Nov;84(5):1595–1608. doi: 10.1172/JCI114337. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Uckun F. M., Fauci A. S., Heerema N. A., Song C. W., Mehta S. R., Gajl-Peczalska K., Chandan M., Ambrus J. L. B-cell growth factor receptor expression and B-cell growth factor response of leukemic B cell precursors and B lineage lymphoid progenitor cells. Blood. 1987 Oct;70(4):1020–1034. [PubMed] [Google Scholar]
  58. Umland S. P., Go N. F., Cupp J. E., Howard M. Responses of B cells from autoimmune mice to IL-5. J Immunol. 1989 Mar 1;142(5):1528–1535. [PubMed] [Google Scholar]
  59. Vazquez A., Auffredou M. T., Galanaud P., Leca G. Modulation of IL-2- and IL-4-dependent human B cell proliferation by cyclic AMP. J Immunol. 1991 Jun 15;146(12):4222–4227. [PubMed] [Google Scholar]
  60. Waldmann T. A., Goldman C. K., Robb R. J., Depper J. M., Leonard W. J., Sharrow S. O., Bongiovanni K. F., Korsmeyer S. J., Greene W. C. Expression of interleukin 2 receptors on activated human B cells. J Exp Med. 1984 Nov 1;160(5):1450–1466. doi: 10.1084/jem.160.5.1450. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Xia X., Li L., Choi Y. S. Human recombinant IL-3 is a growth factor for normal B cells. J Immunol. 1992 Jan 15;148(2):491–497. [PubMed] [Google Scholar]
  62. Yokota T., Otsuka T., Mosmann T., Banchereau J., DeFrance T., Blanchard D., De Vries J. E., Lee F., Arai K. Isolation and characterization of a human interleukin cDNA clone, homologous to mouse B-cell stimulatory factor 1, that expresses B-cell- and T-cell-stimulating activities. Proc Natl Acad Sci U S A. 1986 Aug;83(16):5894–5898. doi: 10.1073/pnas.83.16.5894. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Zlotnik A., Moore K. W. Interleukin 10. Cytokine. 1991 Sep;3(5):366–371. doi: 10.1016/1043-4666(91)90039-g. [DOI] [PubMed] [Google Scholar]

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