Skip to main content
PMC home page
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
. 1989 Oct;86(19):7547–7551. doi: 10.1073/pnas.86.19.7547

IgG1 plasmacytosis in interleukin 6 transgenic mice.

S Suematsu 1, T Matsuda 1, K Aozasa 1, S Akira 1, N Nakano 1, S Ohno 1, J Miyazaki 1, K Yamamura 1, T Hirano 1, T Kishimoto 1
PMCID: PMC298102  PMID: 2798426

Abstract

Interleukin 6 (IL-6) has been suggested to be involved in the pathogenesis of polyclonal and monoclonal plasma cell abnormalities. To address this possibility, transgenic mice carrying the human IL-6 genomic gene fused with a human immunoglobulin heavy chain enhancer were generated. High concentrations of human IL-6 and polyclonal increase in IgG1 (120- to 400-fold) in sera of all transgenic mice were observed. A massive plasmacytosis in thymus, lymph node, and spleen and an infiltration of plasma cells in lung, liver, and kidney were observed. However, the plasma cells were not transplantable to syngeneic mice and were found not to contain chromosomal aberrations including c-myc gene rearrangements. The evidence indicates that deregulated gene expression of IL-6 can trigger polyclonal plasmacytosis but cannot induce plasmacytoma. It is suggested that additional genetic changes may be required for the generation of plasma cell neoplasia. Other interesting findings in these transgenic mice were the development of mesangio-proliferative glomerulonephritis and an increase in megakaryocytes in bone marrow.

Full text

PDF
7547

Images in this article

7548Image
on p.7548
7548Image
on p.7548
7548Image
on p.7548
7548Image
on p.7548
7548Image
on p.7548
7549Image
on p.7549
7549Image
on p.7549
7549Image
on p.7549
7549Image
on p.7549

Selected References

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

  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. Clynes R., Wax J., Stanton L. W., Smith-Gill S., Potter M., Marcu K. B. Rapid induction of IgM-secreting murine plasmacytomas by pristane and an immunoglobulin heavy-chain promoter/enhancer-driven c-myc/v-Ha-ras retrovirus. Proc Natl Acad Sci U S A. 1988 Aug;85(16):6067–6071. doi: 10.1073/pnas.85.16.6067. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. 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]
  4. Graham S. L., Sellers A. L. Atrial myxoma with multiple myeloma. Arch Intern Med. 1979 Jan;139(1):116–117. [PubMed] [Google Scholar]
  5. Hardy R. R., Kishimoto T., Hayakawa K. Differentiation of B cell progenitors in vitro: generation of surface IgM+ B cells, including Ly-1 B cells, from Thy-1- asialoGM1+ cells in newborn liver. Eur J Immunol. 1987 Dec;17(12):1769–1774. doi: 10.1002/eji.1830171214. [DOI] [PubMed] [Google Scholar]
  6. Hayday A. C., Gillies S. D., Saito H., Wood C., Wiman K., Hayward W. S., Tonegawa S. Activation of a translocated human c-myc gene by an enhancer in the immunoglobulin heavy-chain locus. 1984 Jan 26-Feb 1Nature. 307(5949):334–340. doi: 10.1038/307334a0. [DOI] [PubMed] [Google Scholar]
  7. Hirano T., Matsuda T., Turner M., Miyasaka N., Buchan G., Tang B., Sato K., Shimizu M., Maini R., Feldmann M. Excessive production of interleukin 6/B cell stimulatory factor-2 in rheumatoid arthritis. Eur J Immunol. 1988 Nov;18(11):1797–1801. doi: 10.1002/eji.1830181122. [DOI] [PubMed] [Google Scholar]
  8. Hirano T., Taga T., Yasukawa K., Nakajima K., Nakano N., Takatsuki F., Shimizu M., Murashima A., Tsunasawa S., Sakiyama F. Human B-cell differentiation factor defined by an anti-peptide antibody and its possible role in autoantibody production. Proc Natl Acad Sci U S A. 1987 Jan;84(1):228–231. doi: 10.1073/pnas.84.1.228. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. 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]
  10. Ishibashi T., Kimura H., Uchida T., Kariyone S., Friese P., Burstein S. A. Human interleukin 6 is a direct promoter of maturation of megakaryocytes in vitro. Proc Natl Acad Sci U S A. 1989 Aug;86(15):5953–5957. doi: 10.1073/pnas.86.15.5953. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Isobe T., Osserman E. F. Pathologic conditions associated with plasma cell dyscrasias: a study of 806 cases. Ann N Y Acad Sci. 1971 Dec 31;190:507–518. doi: 10.1111/j.1749-6632.1971.tb13560.x. [DOI] [PubMed] [Google Scholar]
  12. Kawano M., Hirano T., Matsuda T., Taga T., Horii Y., Iwato K., Asaoku H., Tang B., Tanabe O., Tanaka H. Autocrine generation and requirement of BSF-2/IL-6 for human multiple myelomas. Nature. 1988 Mar 3;332(6159):83–85. doi: 10.1038/332083a0. [DOI] [PubMed] [Google Scholar]
  13. Keller A. R., Hochholzer L., Castleman B. Hyaline-vascular and plasma-cell types of giant lymph node hyperplasia of the mediastinum and other locations. Cancer. 1972 Mar;29(3):670–683. doi: 10.1002/1097-0142(197203)29:3<670::aid-cncr2820290321>3.0.co;2-#. [DOI] [PubMed] [Google Scholar]
  14. Kishimoto T., Hirano T. Molecular regulation of B lymphocyte response. Annu Rev Immunol. 1988;6:485–512. doi: 10.1146/annurev.iy.06.040188.002413. [DOI] [PubMed] [Google Scholar]
  15. Matsuda T., Hirano T., Kishimoto T. Establishment of an interleukin 6 (IL 6)/B cell stimulatory factor 2-dependent cell line and preparation of anti-IL 6 monoclonal antibodies. Eur J Immunol. 1988 Jun;18(6):951–956. doi: 10.1002/eji.1830180618. [DOI] [PubMed] [Google Scholar]
  16. Mushinski J. F., Bauer S. R., Potter M., Reddy E. P. Increased expression of myc-related oncogene mRNA characterizes most BALB/c plasmacytomas induced by pristane or Abelson murine leukemia virus. Proc Natl Acad Sci U S A. 1983 Feb;80(4):1073–1077. doi: 10.1073/pnas.80.4.1073. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Namba Y., Hanaoka M. Immunocytology of cultured IgM-forming cells of mouse. I. Requirement of phagocytic cell factor for the growth of IgM-forming tumor cells in tissue culture. J Immunol. 1972 Dec;109(6):1193–1200. [PubMed] [Google Scholar]
  18. 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]
  19. 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]
  20. Ohno S., Babonits M., Wiener F., Spira J., Klein G., Potter M. Nonrandom chromosome changes involving the Ig gene-carrying chromosomes 12 and 6 in pristane-induced mouse plasmacytomas. Cell. 1979 Dec;18(4):1001–1007. doi: 10.1016/0092-8674(79)90212-5. [DOI] [PubMed] [Google Scholar]
  21. POTTER M., BOYCE C. R. Induction of plasma-cell neoplasms in strain BALB/c mice with mineral oil and mineral oil adjuvants. Nature. 1962 Mar 17;193:1086–1087. doi: 10.1038/1931086a0. [DOI] [PubMed] [Google Scholar]
  22. Potter M., Mushinski J. F., Mushinski E. B., Brust S., Wax J. S., Wiener F., Babonits M., Rapp U. R., Morse H. C., 3rd Avian v-myc replaces chromosomal translocation in murine plasmacytomagenesis. Science. 1987 Feb 13;235(4790):787–789. doi: 10.1126/science.3810165. [DOI] [PubMed] [Google Scholar]
  23. Potter M., Sklar M. D., Rowe W. P. Rapid viral induction of plasmacytomas in pristane-primed BALB-c mice. Science. 1973 Nov 9;182(4112):592–594. doi: 10.1126/science.182.4112.592. [DOI] [PubMed] [Google Scholar]
  24. Taga T., Kawanishi Y., Hardy R. R., Hirano T., Kishimoto T. Receptors for B cell stimulatory factor 2. Quantitation, specificity, distribution, and regulation of their expression. J Exp Med. 1987 Oct 1;166(4):967–981. doi: 10.1084/jem.166.4.967. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. 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]
  26. 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]
  27. Wanebo H. J., Gallmeier W. M., Boyse E. A., Old L. J. Paraproteinemia and reticulum cell sarcoma in an inbred mouse strain. Science. 1966 Nov 18;154(3751):901–903. doi: 10.1126/science.154.3751.901. [DOI] [PubMed] [Google Scholar]
  28. Wegelius O., Skrifvars B., Andersson L. Rheumatoid arthritis terminating in plasmocytoma. Acta Med Scand. 1970 Jan-Feb;187(1-2):133–138. doi: 10.1111/j.0954-6820.1970.tb02920.x. [DOI] [PubMed] [Google Scholar]
  29. Yamamura K., Kikutani H., Folsom V., Clayton L. K., Kimoto M., Akira S., Kashiwamura S., Tonegawa S., Kishimoto T. Functional expression of a microinjected Ed alpha gene in C57BL/6 transgenic mice. Nature. 1985 Jul 4;316(6023):67–69. doi: 10.1038/316067a0. [DOI] [PubMed] [Google Scholar]
  30. Yamamura K., Kikutani H., Takahashi N., Taga T., Akira S., Kawai K., Fukuchi K., Kumahara Y., Honjo T., Kishimoto T. Introduction of human gamma 1 immunoglobulin genes into fertilized mouse eggs. J Biochem. 1984 Aug;96(2):357–363. doi: 10.1093/oxfordjournals.jbchem.a134845. [DOI] [PubMed] [Google Scholar]
  31. 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]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES