IL-6 Gene Knockout Mice

  • Alistair J. Ramsay
  • Manfred Kopf
Chapter
Part of the Contemporary Immunology book series (CONTIM)

Abstract

Interleukin-6 (IL-6) is a pleiotropic cytokine produced by a variety of cells, including macrophages, T-cells, B-cells, fibroblasts, and endothelial cells, in response to a wide range of stimuli and is thought to play regulatory roles in the immune system, the hematopoietic system, and the nervous system (1). This factor has been given at least nine different names each describing a single biological activity. It was originally identified as a T-cell factor which induced the terminal maturation of B-cells into antibody-producing plasma cells (2),but has also been shown to stimulate the differentiation of cytotoxic T-cells (3), the differentiation and/or proliferation of cells belonging to different hematopoietic lineages (4), and to be the major regulator of acute phase protein synthesis during the inflammatory response (5). In vitro, factors such as IL-1, IL-11, leukemia inhibitory factor (LIF), oncostatin M (OSM) and ciliary neurotrophic factor (CNTF) display overlapping activities with IL-6 that may be explained by a common receptor signal transducing component (gp 130). In order to clarify the unique functions of IL-6 in vivo, we have disrupted the murine IL-6 gene in the second exon by insertion of a neon r cassette and derived mice homozygous for this mutation (6). Although IL-6 may be expressed as early as the eight-cell stage of embryonic development (7), the F1 was generated in the expected Mendelian pattern. Interbreeding resulted in normal numbers of pups with no obvious defects, suggesting that IL-6 is not crucial for embryonic development. In this chapter, we present data describing the roles of IL-6 in B- and T-cell function, hematopoiesis, and acute phase inflammatory responses obtained in studies using these IL-6-/- mice.

Keywords

Leukemia Inhibitory Factor Acute Phase Response Antibody Secreting Cell Plasma Cell Tumor Stern Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Van Snick, J. (1995) Interleukin-6: an overview. Annu. Rev. Immunol. 8, 253 - 278.Google Scholar
  2. 2.
    Schimpl. A. and Wecker, E. (1972) Replacement of a T-cell function by a T-cell product. Nature N. Biol. 237, 15 - 17.Google Scholar
  3. 3.
    Houssiau, F. and Van Snick J. (1992) IL-6 and the T-cell response. Res. Immunol. 143, 740 - 743.PubMedCrossRefGoogle Scholar
  4. 4.
    Kishimoto, T. (1989) The biology of interleukin-6 Blood 74, 1 - 10.PubMedGoogle Scholar
  5. 5.
    Stadnyk, A. and Gauldie, J. (1991) The acute phase protein response during parasitic infection. Immunol. Today 12, A7—Al2.Google Scholar
  6. 6.
    Kopf, M., Baumann, H., Freer, G., Freudenberg, M., Lamers, M., Kishimoto, T., Zinkernagel, R., and Kohler, G. (1994) Impaired immune and acute phase responses in interleukin-6-deficient mice. Nature 368, 339 - 342.Google Scholar
  7. 7.
    Rothstein, J. L., Johnson, D., De Loia, A., Skowronski, J., Salter, D., and Knowles, B. (1992) Gene expression during preimplantation mouse development. Genes Del). 6, 1190 - 1201.CrossRefGoogle Scholar
  8. 8.
    Ikebuchi, K., Wong, G. G., Clark, S. C., Ihie, J. N., Hirai, Y., and Ogawa, M. (1987) Interleukin 6 enhancement of interleukin 3-dependent proliferation of multipotential hemopoietic progenitors. Proc. Natl. Acad. Sci. USA 84, 9035 - 9039.PubMedCrossRefGoogle Scholar
  9. 9.
    Patchen, M. L., McVittie, T. J., Williams, J. L., Schwartz, J. N. and Souza, J. M. (1991) Administration of interleukin-6 stimulates multilineage hematopoiesis and accelerates recovery from radiation-induced hematopoietic depression. Blood 77, 472 - 480.Google Scholar
  10. 10.
    Bernad, A., Kopf, M., Kulbacki, R., Weich, N., Koehler, G. and GuttierezRamos, J. C. (1994) Interleukin-6 is required in vivo for the regulation of stem cells and committed progenitors of the hematopoietic system. Immunity 1, 725 - 731.PubMedCrossRefGoogle Scholar
  11. 11.
    Uttenhove, C. P., Coulie, P. G., and Van Snick, J. (1988) T cell growth and differentiation induced by interleukin HP1/IL-6, the murine hybridoma/plasmocytoma growth factor. J. Exp. Med. 167, 1417 - 1427.Google Scholar
  12. 12.
    Lotz, M., Jirik, F., Kabouridis, P., Tsoukas, C., Hirano, T., Kishimoto, T., and Carson, D. A. (1988) B cell stimulating factor 2/interleukin 6 is a costimulant for human thymocytes and T lymphocytes. J. Exp. Med. 167, 1253 - 1258.PubMedCrossRefGoogle Scholar
  13. 13.
    Ramsay, A. J., Ruby, J., and Ramshaw, I. A. (1993) A case for cytokines as effector molecules in the resolution of virus infection. Immunol. Today 14, 155 - 157.Google Scholar
  14. 14.
    Dalton, D. K., Pitts, M. S., Keshav, S., Figari., I. S., Bradley, A., and Stewart, T. A. (1993) Multiple defects of immune cell function in mice with disrupted interferon-gamma genes. Science 259, 1739 - 1742.Google Scholar
  15. 15.
    MacLennan, I. C. (1994) Germinal centres. Annu. Rev. Immunol. 12, 117 - 139.PubMedCrossRefGoogle Scholar
  16. 16.
    Kopf, M., Ramsay, A. J., Brombacher, F., Baumann, H., Freer, G., Galanos, C., Guttierez-Ramos, J., and Kohler, G. (1995) Pleiotropic defects of IL-6deficient mice including early hematopoietis. T and B cell function and acute phase responses. Ann. N.Y. Acad. Sci. 762, 308 - 318.Google Scholar
  17. 17.
    Jourdan, M., Bataille, R., Seguin, J., Zhang, X. G., Chaptal, P. A., and Klein, B. (1990) Constitutive production of interleukin-6 and immunologic features in cardiac myxomas. Arthritis Rheum. 33, 398 - 402.Google Scholar
  18. 18.
    Suematsu, S., Matsusaka, T., Matsuda, T., Ohno, S., Miyazaki, J., Yamamura, K., Hirano, T., and Kishimoto, T. (1992) Generation of plasmacytomas with the chromosomal translocation t(12;15) in interleukin 6 trans-genic mice. Proc. Natl. Acad. Sci. USA 89, 232 - 235.PubMedCrossRefGoogle Scholar
  19. 19.
    Klein, B., Zhang, X. G., Lu, Z. Y., and Bataille, R. (1995) Interleukin-6 in human multiple myeloma. Blood 85, 863 - 872.PubMedGoogle Scholar
  20. 20.
    Kishimoto, T., Akira, S., and Taga, T. (1992) Interleukin-6 and its receptor: a paradigm for cytokines. Science 258, 593 - 597.Google Scholar
  21. 21.
    Hilbert, D. M., Kopf, M., Mock, B. A., Kohler, G., and Rudikoff, S. (1995) Interleukin 6 is essential for in vivo development of B lineage neoplasms. J. Exp. Med. 182, 243 - 248.PubMedCrossRefGoogle Scholar
  22. 22.
    Brandtzaeg, P. (1989) Overview of the mucosal immune system. Curr. Top. Microbiol. Immunol. 146, 13 - 25.PubMedCrossRefGoogle Scholar
  23. 23.
    Taguchi, T., McGhee, J. R., Coffman, R. L., Beagley, K. W., Eldridge, J. H., Takatsu, K., and Kiyono, H. (1990) Analysis of Thl and Th2 cells in murine gut-associated tissues. Frequencies of CD4+ and CD8+ T cells that secrete IFN-y and IL-5. J. Immunol. 145, 68 - 77.Google Scholar
  24. 24.
    Xu-Amano, J., Kiyono, H., Jackson, R. J., Staats, H. F., Fujihashi, K., Burrows, P. D., Elson, C. O., Pillai, S., and McGhee, J. R. (1992) Helper T cell subsets for immunoglobulin A responses: oral immunization with tetanus toxoid and cholera toxin as adjuvant selectively induces Th2 cells in mucosa associated tissues. J. Exp. Med. 172, 921-929.Google Scholar
  25. 25.
    Bao, S., Goldstone, S., and Husband, A. J. (1993) Localisation of IFN-y and IL-6 in murine intestine by in situ hybridisation. Immunology 80, 666 - 670.PubMedGoogle Scholar
  26. Beagley, K. W., Eldridge, J. H., Lee, F., Kiyono, H., Everson, M. P., Koopman, W. J., Hirano, T., Kishimoto, T., and McGhee, J. R. (1989) Interleukins and IgA synthesis: human and murine IL-6 induce high rate IgA secretion in IgA-committed B cells. J. Exp. Med. 169, 2133-2148.Google Scholar
  27. Kunimoto, D. Y., Nordan, R. P., and Strober, W. (1989) IL-6 is a potent cofactor of IL-1 in IgM synthesis and of IL-5 in IgA synthesis. J. Immunol. 143, 2230-2235.Google Scholar
  28. 28.
    Fujihashi, K., McGhee, J. R., Lue, C., Beagley, K. W., Taga, T., Hirano, T., Kishimoto, T., Mestecky, J., and Kiyono, H. (1991) Human appendix B cells naturally express receptors for and respond to interleukin 6 with selective IgAl and IgA2 synthesis. J. Clin. Invest. 88, 248 - 252.PubMedCrossRefGoogle Scholar
  29. 29.
    Mega, J., McGhee, J. R., and Kiyono, H. (1992) Cytokine-and Ig-producing T cells in mucosal effector tissues: analysis of IL-5- and IFN-gammaproducing T cells, T cell receptor expression, and IgA plasma cells from mouse salivary gland-associated tissues. J. Immunol. 148, 2030 - 2039.PubMedGoogle Scholar
  30. Ramsay, A. J., Husband, A. J., Ramshaw, I. A., Bao, S., Matthaei, K., Kohler, G., and Kopf, M. (1994) The role of interleukin-6 in mucosal IgA responses in vivo. Science 264, 561-563.Google Scholar
  31. 31.
    Beagley, K. W., Bao, S., Ramsay, A. J., Eldridge, J. H., and Husband, A. J. (1995) IgA production by peritoneal cavity B cells is IL-6-independent: implications for intestinal IgA responses. Eur. J. Immunol. 25, 2123 - 2126.Google Scholar
  32. 32.
    Pecquet, S. S., Ehrat, C., and Ernst, P. B. (1992) Enhancement of mucosal antibody responses to Salmonella typhimurium and the microbial hapten phosphorylcholine in mice with X-linked immunodeficiency by B-cell precursors from the peritoneal cavity. Infect. Immun. 60, 503 - 509.PubMedGoogle Scholar
  33. Bromander, A. K., Ekman, L., Kopf, M., Nedrud, J. G., and Lycke, N. Y. (1996) IL-6 deficient mice exhibit normal mucosal IgA responses to local immunizations and Helicobacter felis infection. J. Immunol. 156, 4290-4297.Google Scholar
  34. 34.
    Ramshaw, I. A., Ruby, J., Ramsay, A. J., Ada, G. L., and Karupiah, G. (1992) Expression of cytokines by recombinant vaccinia viruses: a model for studying cytokines in virus infections in vivo. Immunol. Rev. 127, 157 - 182.PubMedCrossRefGoogle Scholar
  35. 35.
    Romani, L., Mencacci, A., Cenci, E., Spaccapelo, R., Toniatti, C., Puccetti, P., Bistoni, F., and Poli, V. (1996) Impaired neutrophil responses and CD4+ T helper cell development in interleukin 6-deficient mice infected with Candida Albecans. J. Exp. Med. 183, 1345 - 1355.CrossRefGoogle Scholar
  36. 36.
    Koj, A. (1985) The acute phase response to injury and infection, in Injury and Infection ( Gordon, A. H. and Koj, A., eds.), Elsevier, Amsterdam, pp. 145 - 160.Google Scholar

Copyright information

© Springer Science+Business Media New York 1998

Authors and Affiliations

  • Alistair J. Ramsay
  • Manfred Kopf

There are no affiliations available

Personalised recommendations