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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
. 1988 Oct;85(19):7099–7103. doi: 10.1073/pnas.85.19.7099

Multiple biological activities are expressed by a mouse interleukin 6 cDNA clone isolated from bone marrow stromal cells.

C P Chiu 1, C Moulds 1, R L Coffman 1, D Rennick 1, F Lee 1
PMCID: PMC282131  PMID: 3262872

Abstract

Interleukin 6 (IL-6) refers to the gene product that was characterized initially as beta 2 interferon/26-kDa protein produced by human fibroblasts and later was found to be identical to B-cell stimulatory factor 2, hybridoma/plasmacytoma growth factor, and probably hepatocyte-stimulating factor. Using the human IL-6 cDNA as a probe, we have isolated functional cDNA clones from mouse bone marrow stromal cell cDNA libraries. Sequence analysis of the mouse cDNA insert revealed significant homology between the human and mouse IL-6 cDNA clones both at the level of nucleotide (65%) and deduced amino acid (41%) sequences. The NH2-terminal sequence of the deduced protein is identical to a partial NH2-terminal sequence determined previously for a hybridoma/plasmacytoma growth factor and a plasmacytoma growth factor isolated from mouse T cells and macrophages, respectively. The mRNA for mouse IL-6 is expressed in IL-1-treated stromal cells and in activated T-cell and macrophage cell lines. Supernatants from COS-7 monkey cells transfected with the cDNA clone have plasmacytoma growth factor, hepatocyte-stimulating factor, and colony-stimulating factor activities, as well as the ability to support the growth of a factor-dependent myeloid cell line, thus revealing an additional biological activity for IL-6.

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Selected References

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  1. Andus T., Geiger T., Hirano T., Northoff H., Ganter U., Bauer J., Kishimoto T., Heinrich P. C. Recombinant human B cell stimulatory factor 2 (BSF-2/IFN-beta 2) regulates beta-fibrinogen and albumin mRNA levels in Fao-9 cells. FEBS Lett. 1987 Aug 31;221(1):18–22. doi: 10.1016/0014-5793(87)80344-7. [DOI] [PubMed] [Google Scholar]
  2. Baumann H., Hill R. E., Sauder D. N., Jahreis G. P. Regulation of major acute-phase plasma proteins by hepatocyte-stimulating factors of human squamous carcinoma cells. J Cell Biol. 1986 Feb;102(2):370–383. doi: 10.1083/jcb.102.2.370. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Berk A. J., Sharp P. A. Sizing and mapping of early adenovirus mRNAs by gel electrophoresis of S1 endonuclease-digested hybrids. Cell. 1977 Nov;12(3):721–732. doi: 10.1016/0092-8674(77)90272-0. [DOI] [PubMed] [Google Scholar]
  4. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  5. Defilippi P., Poupart P., Tavernier J., Fiers W., Content J. Induction and regulation of mRNA encoding 26-kDa protein in human cell lines treated with recombinant human tumor necrosis factor. Proc Natl Acad Sci U S A. 1987 Jul;84(13):4557–4561. doi: 10.1073/pnas.84.13.4557. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Dexter T. M., Garland J., Scott D., Scolnick E., Metcalf D. Growth of factor-dependent hemopoietic precursor cell lines. J Exp Med. 1980 Oct 1;152(4):1036–1047. doi: 10.1084/jem.152.4.1036. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Fey G. H., Fuller G. M. Regulation of acute phase gene expression by inflammatory mediators. Mol Biol Med. 1987 Dec;4(6):323–338. [PubMed] [Google Scholar]
  8. Garman R. D., Jacobs K. A., Clark S. C., Raulet D. H. B-cell-stimulatory factor 2 (beta 2 interferon) functions as a second signal for interleukin 2 production by mature murine T cells. Proc Natl Acad Sci U S A. 1987 Nov;84(21):7629–7633. doi: 10.1073/pnas.84.21.7629. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Garman R. D., Raulet D. H. Characterization of a novel murine T cell-activating factor. J Immunol. 1987 Feb 15;138(4):1121–1129. [PubMed] [Google Scholar]
  10. Gauldie J., Richards C., Harnish D., Lansdorp P., Baumann H. Interferon beta 2/B-cell stimulatory factor type 2 shares identity with monocyte-derived hepatocyte-stimulating factor and regulates the major acute phase protein response in liver cells. Proc Natl Acad Sci U S A. 1987 Oct;84(20):7251–7255. doi: 10.1073/pnas.84.20.7251. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Greenberger J. S., Sakakeeny M. A., Humphries R. K., Eaves C. J., Eckner R. J. Demonstration of permanent factor-dependent multipotential (erythroid/neutrophil/basophil) hematopoietic progenitor cell lines. Proc Natl Acad Sci U S A. 1983 May;80(10):2931–2935. doi: 10.1073/pnas.80.10.2931. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hirano T., Yasukawa K., Harada H., Taga T., Watanabe Y., Matsuda T., Kashiwamura S., Nakajima K., Koyama K., Iwamatsu A. Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin. Nature. 1986 Nov 6;324(6092):73–76. doi: 10.1038/324073a0. [DOI] [PubMed] [Google Scholar]
  13. Hodgkin P. D., Bond M. W., O'Garra A., Frank G., Lee F., Coffman R. L., Zlotnik A., Howard M. Identification of IL-6 as a T cell-derived factor that enhances the proliferative response of thymocytes to IL-4 and phorbol myristate acetate. J Immunol. 1988 Jul 1;141(1):151–157. [PubMed] [Google Scholar]
  14. Hunt P., Robertson D., Weiss D., Rennick D., Lee F., Witte O. N. A single bone marrow-derived stromal cell type supports the in vitro growth of early lymphoid and myeloid cells. Cell. 1987 Mar 27;48(6):997–1007. doi: 10.1016/0092-8674(87)90708-2. [DOI] [PubMed] [Google Scholar]
  15. Ikebuchi K., Wong G. G., Clark S. C., Ihle J. N., Hirai Y., Ogawa M. Interleukin 6 enhancement of interleukin 3-dependent proliferation of multipotential hemopoietic progenitors. Proc Natl Acad Sci U S A. 1987 Dec;84(24):9035–9039. doi: 10.1073/pnas.84.24.9035. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kaye J., Porcelli S., Tite J., Jones B., Janeway C. A., Jr Both a monoclonal antibody and antisera specific for determinants unique to individual cloned helper T cell lines can substitute for antigen and antigen-presenting cells in the activation of T cells. J Exp Med. 1983 Sep 1;158(3):836–856. doi: 10.1084/jem.158.3.836. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Koyasu S., Nakauchi H., Kitamura K., Yonehara S., Okumura K., Tada T., Yahara I. Production of interleukin 3 and gamma-interferon by an antigen-specific mouse suppressor T cell clone. J Immunol. 1985 May;134(5):3130–3136. [PubMed] [Google Scholar]
  18. Lee F., Yokota T., Otsuka T., Gemmell L., Larson N., Luh J., Arai K., Rennick D. Isolation of cDNA for a human granulocyte-macrophage colony-stimulating factor by functional expression in mammalian cells. Proc Natl Acad Sci U S A. 1985 Jul;82(13):4360–4364. doi: 10.1073/pnas.82.13.4360. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Lee M., Segal G. M., Bagby G. C. Interleukin-1 induces human bone marrow-derived fibroblasts to produce multilineage hematopoietic growth factors. Exp Hematol. 1987 Oct;15(9):983–988. [PubMed] [Google Scholar]
  20. Metcalf D. Colony formation in agar by murine plasmacytoma cells: potentiation by hemopoietic cells and serum. J Cell Physiol. 1973 Jun;81(3):397–410. doi: 10.1002/jcp.1040810312. [DOI] [PubMed] [Google Scholar]
  21. Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983 Dec 16;65(1-2):55–63. doi: 10.1016/0022-1759(83)90303-4. [DOI] [PubMed] [Google Scholar]
  22. Nabel G., Greenberger J. S., Sakakeeny M. A., Cantor H. Multiple biologic activities of a cloned inducer T-cell population. Proc Natl Acad Sci U S A. 1981 Feb;78(2):1157–1161. doi: 10.1073/pnas.78.2.1157. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Nordan R. P., Potter M. A macrophage-derived factor required by plasmacytomas for survival and proliferation in vitro. Science. 1986 Aug 1;233(4763):566–569. doi: 10.1126/science.3726549. [DOI] [PubMed] [Google Scholar]
  24. Nordan R. P., Pumphrey J. G., Rudikoff S. Purification and NH2-terminal sequence of a plasmacytoma growth factor derived from the murine macrophage cell line P388D1. J Immunol. 1987 Aug 1;139(3):813–817. [PubMed] [Google Scholar]
  25. Okayama H., Berg P. A cDNA cloning vector that permits expression of cDNA inserts in mammalian cells. Mol Cell Biol. 1983 Feb;3(2):280–289. doi: 10.1128/mcb.3.2.280. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Poupart P., Vandenabeele P., Cayphas S., Van Snick J., Haegeman G., Kruys V., Fiers W., Content J. B cell growth modulating and differentiating activity of recombinant human 26-kd protein (BSF-2, HuIFN-beta 2, HPGF). EMBO J. 1987 May;6(5):1219–1224. doi: 10.1002/j.1460-2075.1987.tb02357.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Rennick D., Yang G., Gemmell L., Lee F. Control of hemopoiesis by a bone marrow stromal cell clone: lipopolysaccharide- and interleukin-1-inducible production of colony-stimulating factors. Blood. 1987 Feb;69(2):682–691. [PubMed] [Google Scholar]
  28. Rennick D., Yang G., Muller-Sieburg C., Smith C., Arai N., Takabe Y., Gemmell L. Interleukin 4 (B-cell stimulatory factor 1) can enhance or antagonize the factor-dependent growth of hemopoietic progenitor cells. Proc Natl Acad Sci U S A. 1987 Oct;84(19):6889–6893. doi: 10.1073/pnas.84.19.6889. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. 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]
  30. Sehgal P. B., May L. T., Tamm I., Vilcek J. Human beta 2 interferon and B-cell differentiation factor BSF-2 are identical. Science. 1987 Feb 13;235(4790):731–732. doi: 10.1126/science.3492764. [DOI] [PubMed] [Google Scholar]
  31. Takebe Y., Seiki M., Fujisawa J., Hoy P., Yokota K., Arai K., Yoshida M., Arai N. SR alpha promoter: an efficient and versatile mammalian cDNA expression system composed of the simian virus 40 early promoter and the R-U5 segment of human T-cell leukemia virus type 1 long terminal repeat. Mol Cell Biol. 1988 Jan;8(1):466–472. doi: 10.1128/mcb.8.1.466. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Van Damme J., Cayphas S., Van Snick J., Conings R., Put W., Lenaerts J. P., Simpson R. J., Billiau A. Purification and characterization of human fibroblast-derived hybridoma growth factor identical to T-cell-derived B-cell stimulatory factor-2 (interleukin-6). Eur J Biochem. 1987 Nov 2;168(3):543–550. doi: 10.1111/j.1432-1033.1987.tb13452.x. [DOI] [PubMed] [Google Scholar]
  33. Van Damme J., Opdenakker G., Simpson R. J., Rubira M. R., Cayphas S., Vink A., Billiau A., Van Snick J. Identification of the human 26-kD protein, interferon beta 2 (IFN-beta 2), as a B cell hybridoma/plasmacytoma growth factor induced by interleukin 1 and tumor necrosis factor. J Exp Med. 1987 Mar 1;165(3):914–919. doi: 10.1084/jem.165.3.914. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Van Snick J., Cayphas S., Szikora J. P., Renauld J. C., Van Roost E., Boon T., Simpson R. J. cDNA cloning of murine interleukin-HP1: homology with human interleukin 6. Eur J Immunol. 1988 Feb;18(2):193–197. doi: 10.1002/eji.1830180202. [DOI] [PubMed] [Google Scholar]
  35. Van Snick J., Cayphas S., Vink A., Uyttenhove C., Coulie P. G., Rubira M. R., Simpson R. J. Purification and NH2-terminal amino acid sequence of a T-cell-derived lymphokine with growth factor activity for B-cell hybridomas. Proc Natl Acad Sci U S A. 1986 Dec;83(24):9679–9683. doi: 10.1073/pnas.83.24.9679. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Yasukawa K., Hirano T., Watanabe Y., Muratani K., Matsuda T., Nakai S., Kishimoto T. Structure and expression of human B cell stimulatory factor-2 (BSF-2/IL-6) gene. EMBO J. 1987 Oct;6(10):2939–2945. doi: 10.1002/j.1460-2075.1987.tb02598.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Yokota T., Lee F., Rennick D., Hall C., Arai N., Mosmann T., Nabel G., Cantor H., Arai K. Isolation and characterization of a mouse cDNA clone that expresses mast-cell growth-factor activity in monkey cells. Proc Natl Acad Sci U S A. 1984 Feb;81(4):1070–1074. doi: 10.1073/pnas.81.4.1070. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Zilberstein A., Ruggieri R., Korn J. H., Revel M. Structure and expression of cDNA and genes for human interferon-beta-2, a distinct species inducible by growth-stimulatory cytokines. EMBO J. 1986 Oct;5(10):2529–2537. doi: 10.1002/j.1460-2075.1986.tb04531.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Zucali J. R., Dinarello C. A., Oblon D. J., Gross M. A., Anderson L., Weiner R. S. Interleukin 1 stimulates fibroblasts to produce granulocyte-macrophage colony-stimulating activity and prostaglandin E2. J Clin Invest. 1986 Jun;77(6):1857–1863. doi: 10.1172/JCI112512. [DOI] [PMC free article] [PubMed] [Google Scholar]

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