The Transforming Growth Factor-β1 Knockout Mouse

The Phenotype and Its Implications for TGFβ1 Function
  • Ashok B. Kulkarni
  • John J. Letterio
Part of the Contemporary Immunology book series (CONTIM)


Transforming growth factor-β (TGFβ) represents the prototype in a large superfamily of secreted signaling molecules (1). Sharing several conserved structural features, these molecules act to control important events during growth and development, and in some instances function to maintain normal homeostasis in the adult. Each of the over 20 members of this extended family, which includes the activins, the inhibins, Mullerian inhibiting substance (MIS), and the decapentaplegic peptide of Drosopholia (DPP), has been found to regulate events as critical as sexual development, pituitary hormone production, and bone and cartilage formation (2).


Knockout Mouse Major Histocompatibility Complex Class Transform Growth Factor Deficient Mouse Hereditary Haemorrhagic Telangiectasia 
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  1. 1.
    Roberts, A. B. and Sporn, M. B. (1990) The transforming growth factor (3s, in Peptide Growth Factors and Their Receptors ( Sporn, M. B. and Roberts, A. B., eds.), Springer-Verlag, Heidelberg, Germany, pp. 419–472.CrossRefGoogle Scholar
  2. 2.
    Kingsley, D. M. (1994) The TGF-(3 superfamily• new members, new receptors, and new genetic tests of function in different organisms. Genes Dev. 8, 133–146.PubMedCrossRefGoogle Scholar
  3. 3.
    Millan, F. A., Denhez, F., Kondaiah, P., and Akhurst, R. J. (1991) Embryonic gene expression patterns of TGF (31, 132, and 133 suggest different developmental functions in vivo. Development 111, 131–144.Google Scholar
  4. 4.
    Schmid, P., Cox, D., Bilbe, G., Rainer, M., and McMaster, G. K. (1991) Differential expression of TGF 131, (32 and (33 genes during mouse embryo-genesis. Development 11, 117–130.Google Scholar
  5. 5.
    Roberts, A. B., Lamb, L. C., Newton, D. L., Sporn, M. B., DeLarco, J. E., and Todaro, G. J. (1980) Transforming growth factors; Isolation of polypeptides from virally and chemically transformed cells by acid/ethanol extraction. Proc. Natl. Acad. Sci. USA 77, 3494–3498.PubMedCrossRefGoogle Scholar
  6. 6.
    Nathan, C. and Sporn, M. (1991) Cytokines in context. J. Cell Biol. 113, 981–986.PubMedCrossRefGoogle Scholar
  7. 7.
    Moses, H. L., Yang, E. Y., and Pietenpol, J. A. (1990) TGF-beta stimulation and inhibition of cell proliferation: new mechanistic insights. Cell 63, 245–247.PubMedCrossRefGoogle Scholar
  8. 8.
    Sporn, M. B. and Roberts, A. B. (1990) TGF-ß: problems and prospects. Cell Regulation 1, 875–882.PubMedGoogle Scholar
  9. 9.
    Roberts, A. B. and Sporn, M. B. (1992) Differential expression of the TGF(. isoforms in embryogenesis suggests specific roles in developing and adult tissues. Mol. Reprod. Dev. 32, 91–98.PubMedCrossRefGoogle Scholar
  10. 10.
    Sporn, M. B. and Roberts, A. B. (1993) A major advance in the use of growth factors to enhance wound healing. J. Clin. Invest. 92, 2565–2566.PubMedCrossRefGoogle Scholar
  11. 11.
    Barnard, J. A., Beauchamp, R. D., Coffey, R. J., and Moses, H. L. (1989) Regulation of intestinal epithelial cell growth by transforming growth factor type beta. Proc. Natl. Acad. Sci. USA 86, 1578–1582.PubMedCrossRefGoogle Scholar
  12. 12.
    Ruscetti, F. W., Jacobsen, S. E., Birchenall-Roberts, M., Broxmeyer, H. E., Engelmann, G. I., Dubois, C., and Deller, J. R. (1991) Role of transforming growth factor-(31 in the regulation of hematopoiesis. Ann. N.Y. Acad. Sci. 628, 31.PubMedCrossRefGoogle Scholar
  13. 13.
    Takahama, Y., Letterio, J. J., Harumi Suzuki, H., Farr, A. G., and Singer, A. (1994) Early progression of thymocytes along the CD4/CD8 developmental pathway is regulated by a subset of thymic epithelial cells expressing transforming growth factor 13. J. Exp. Med. 179, 1495–1506.PubMedCrossRefGoogle Scholar
  14. 14.
    Fontana, A., Constam, D. B., Frei, K., Malipiero, U., and Pfister, H. W. (1992) Modulation of the immune response by transforming growth factor beta. Int. Arch. Allergy Immunol. 99, 1–7.PubMedCrossRefGoogle Scholar
  15. 15.
    Wahl, S. M. (1994) Transforming growth factor 13: the good, the bad, and the ugly. J. Exp. Med 180, 1587–1590.PubMedCrossRefGoogle Scholar
  16. 16.
    Capocasale, R. J., Lamb, R. J., Vonderheid, E. C., Fox, F. E., Rook, A. H., Nowell, P. C., and Moore, J. S. (1995) Reduced surface expression of transforming growth factor receptor type II in mitogen-activated T-cells from Sézary patients. Proc. Natl. Acad. Sci. USA 92, 5501–5505.PubMedCrossRefGoogle Scholar
  17. 17.
    Kadin, M. E., Cavaille-Coll, M. W., Gertz, R., Massagué, J., Cheifetz, S., and George, D. (1994) Loss of receptors for transforming growth factor 13 in human T-cell malignancies. Proc. Natl. Acad. Sci. USA 91, 6002–6006.PubMedCrossRefGoogle Scholar
  18. 18.
    Markowitz, S., Wang, J., Myeroff, L., Parsons, R., Sun, L., Lutterbaugh, J., Fan, R. S., Zborowska, E., Kinzler, K. W., Vogelstein, B., Brattain, M., and Willson, J. K. V. (1995) Inactivation of the type II TGF-13 receptor in colon cancer cells with microsatellite instability. Science 268, 1336–1338.PubMedCrossRefGoogle Scholar
  19. 19.
    McAllister, K. A., Grogg, K. M., Johnson, D. W., Gallione, C. J., Baldwin, M. A., Jackson, C. E., Helmbold, E. A., Markel, D. S., McKinnon, W. C., Murrell, J., McCormick, M. K., Pericak-Vance, M. A., Heutink, P, Oostra, B. A., Haitjema, T., Westerman, C. J. J., Porteous, M. E., Guttmacher, A. E., Letarte, M., and Marchuk, D. A. (1994) Endoglin, a TGF-13 binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nature Genet. 8, 351.Google Scholar
  20. 20.
    Alexandrow, M. G. and Moses, H. L. (1995) Transforming growth factor ß and cell cycle regulation. Cancer Res. 55, 1452–1457.PubMedGoogle Scholar
  21. 21.
    Miyazono, K., Hidenori, I., and Heldin, C. (1993) Transforming growth factor-13: latent forms, binding proteins and receptors. Growth Factors 8, 11–22.PubMedCrossRefGoogle Scholar
  22. 22.
    Miyazono, K., Hellman, U., Wernstedt, C., and Heldin, C. (1988) Latent high molecular weight complex of transforming growth factor purification from human platelets and structural characterization. J. Biol. Chem. 263, 6407–6415.PubMedGoogle Scholar
  23. 23.
    Erickson, H. P. (1993) Gene knockouts of c-src, transforming growth factor, and tenascin suggest superfluous, non-functional expression of proteins. J. Cell Biol. 120, 1079–1081.PubMedCrossRefGoogle Scholar
  24. 24.
    Kim, S. J., Angel, P., Lafyatis, R., Hattori, K., Kim, K. Y., Sporn, M. B., Karin, M., and Roberts, A. B. (1990) Autoinduction of transforming growth factor 131 is mediated by the AP-1 complex. Mol. Cell. Biol. 10, 1492–1497.PubMedGoogle Scholar
  25. 25.
    McCartney-Francis, N. L. and Wahl, S. M. (1994) Transforming growth factor 13: a matter of life and death. J. Leukoc. Biol. 55, 401–409.PubMedGoogle Scholar
  26. 26.
    Roberts, A. B., and Sporn, M. B. (1993) Physiological actions and clinical applications of transforming growth factor-13 (TGF-13). Growth Factors 8, 1–9.PubMedCrossRefGoogle Scholar
  27. 27.
    Border, W. A. and Noble, N. A. (1994) Transforming growth factor 13 in tissue fibrosis. N. Engl. J. Med. 331, 1286–1292.PubMedCrossRefGoogle Scholar
  28. 28.
    Kulkarni, A. B., Huh, C., Becker, D., Geiser, A., Lyght, M., Flanders, K. C., Roberts, A. B., Sporn, M. B., Ward, J. M., and Karlsson, S. (1993) Transforming growth factor 131 null mutation in mice causes excessive inflammatory response and early death. Proc. Natl. Acad. Sci. USA 90, 770–774.PubMedCrossRefGoogle Scholar
  29. 29.
    Schull, M. M., Ormsby, I., Kier, A. B., Pawlowski, S., Diebold, R. J., Yin, M., Allen, R., Sidman, C., Proetzel, B., Calvin, D., Annunziata, N., and Doetschman, T. (1992) Targeted disruption of the mouse transforming growth factor-131 gene results in multifocal inflammatory disease. Nature 359, 693–699.CrossRefGoogle Scholar
  30. 30.
    Proetzel, G., Pawlowski, S. A., Wiles, M. V., Yin, M., Boivin, G. P., Howles, P. N., Ding, J., Ferguson, W. J., and Doetschman, T. (1995) Transforming growth factor-(33 is required for secondary palate fusion. Nature Genet. 11, 409–414.PubMedCrossRefGoogle Scholar
  31. 31.
    Kaartinen, V., Voncken, J. W., Shuler, C., Warburton, D., Bu, D., Heisterkamp, N., and Groffen, J. (1995) Abnormal lung development and cleft palate in mice lacking TGF-133 indicates defects of epithelialmesenchymal interaction. Nature Genet. 11, 415–420.PubMedCrossRefGoogle Scholar
  32. 32.
    Kulkarni, A. B., Ward, J. M., Geiser, A. G., Letterio, J. J., Hines, K. L., Christ, M., D’ Souza, R. N., Huh, C., Roberts, A. B., Sporn, M. B., McCartney-Francis, N., Wahl, S. M., Glick, A. B., Yuspa, S. H., Mackall, C., Gress, R. E., and Karlsson, S. (1994) TGF-131 knockout mice. Immune dysregulation and pathology, in Molecular Biology of Haematopoiesis ( Abraham, N. G., Shaddduck, R. K., Levine, A. S., and Takaku, F., eds.) Intecept, Paris. pp. 749–757.Google Scholar
  33. 33.
    Shull, M. M., Kier, A. B., Diebold, R. J., Moying, Y., and Doetschman, T. (1994) The importance of transforming growth factor 131 in immunological homeostasis, as revealed by gene ablation in mice, in Overexpression and Knockout of Cytokines in Transgenic Mice ( Jacon, C., ed.), Academic Chicago, IL, pp. 135–159.Google Scholar
  34. 34.
    Espevik, T., Figari, I. S., Shalaby, M. R., Lakides, G. A., Lewis, G. D., Shepard, H. M., and Palladino, M. A. (1987) Inhibition of cytokine production by cyclosporin A and transforming growth factor (3. J. Exp. Med. 166, 571–576.PubMedCrossRefGoogle Scholar
  35. 35.
    Espevik, T., Waage, A., Faxvaag, A., and Shalaby, M. R. (1990) Regulation of interleukin-2 and interleukin-6 production from T-cells: involvement of interleukin-1 ß and transforming growth factor-ß. Cell. Immunol. 126, 47–56.PubMedCrossRefGoogle Scholar
  36. 36.
    Tsunawaki, S., Sporn, M., Ding, A., and Nathan, C. (1988) Deactivation of macrophages by transforming growth factor-(3. Nature 334, 260–262.PubMedCrossRefGoogle Scholar
  37. 37.
    Vodovotz, Y., Bogdan, C., Paik, J., Xie, Q.-W., and Nathan, C. (1993) Mechanisms of suppression of macrophage nitric oxide release by transforming growth factor ß. J. Exp. Med. 178, 605–613.PubMedCrossRefGoogle Scholar
  38. 38.
    Gamble, J. R., Khew-Goodall, Y., and Vadas, M. A. (1993) Transforming growth factor-(3 inhibits E-selectin expression on human endothelial cells. J. Immunol. 150, 4494–4503.PubMedGoogle Scholar
  39. 39.
    Wahl, S. M., Allen, J. B., Weeks, B. S., Wong, H. L., and Klotman, P. E. (1993) Transforming growth factor I3 enhances integrin expression and type IV collagenase secretion in human monocytes. Proc. Natl. Acad. Sci. USA 90, 4577–4581.PubMedCrossRefGoogle Scholar
  40. 40.
    Wahl, S. M., Hines, K. L., Christ, M., McCartney-Francis, N., Kulkarni, A., Karlsson, S., Furcht, L., and McCarthy, J. B. (1993) Adhesion, recruitment, and activation of mononuclear phagocytes in inflammation. J. Leukoc. Biol. 54 (Suppl.), 74–81.Google Scholar
  41. 41.
    Kehrl, J. H., Thevenin, C., Rieckmann, P., and Fauci, A. S. (1991) Transforming growth factor 13 suppresses human B-lymphocyte Ig production by inhibiting synthesis and the switch from the membrane form to the secretion form of Ig mRNA. J. Immunol. 146, 4016 1023.Google Scholar
  42. 42.
    Ortaldo, J. R., Mason, A. T., O’Shea, J. J., Smyth, M. J., Falk, L. A., Kennedy, I. C. S., Longo, D. L., and Ruscetti, F. W. (1991) Mechanistic studies of transforming growth factor beta inhibition of IL-2-dependent activation of CD3-large granular lymphocyte functions. Regulation of IL-2R beta (p75) signal transduction. J. Immunol. 146, 3791–3798.PubMedGoogle Scholar
  43. 43.
    Wallik, S. C., Figari, I. S., Morris, R. E., Levinson, A. D., and Palladino, M. A. (1990) Immunoregulatory role of transforming growth factor 13 (TGF-(3) in development of killer cells: comparison of active and latent TGF-(31. J. Exp. Med. 172, 1777–1784.CrossRefGoogle Scholar
  44. 44.
    Wahl, S. M., Allen, J. B., Costa, G. L., Wong, H. L., and Dasch, J. R. (1993) Reversal of acute and chronic synovial inflammation by anti-transforming growth factor P. J. Exp. Med. 177, 225–230.PubMedCrossRefGoogle Scholar
  45. 45.
    Roberts, A. B., Sporn, A. B., and Lefer, A. M. (1993) Cardioprotective actions of transforming growth factor-(3. Trends Cardiovasc. Med. 3, 77–81.PubMedCrossRefGoogle Scholar
  46. 46.
    Brandes, M. E., Allen, J. B., Ogawa, Y., and Wahl, S. M. (1991) Transforming growth factor beta 1 suppresses acute and chronic arthritis in experimental animals. J. Clin. Invest. 87, 1108–1113.PubMedCrossRefGoogle Scholar
  47. 47.
    Hines, K. L., Kulkarni, A. B., McCarthy, J. B., Tian, H., Ward, J. M., Christ, M., McCartney-Francis, N. L., Furcht, L. T., Karlsson, S., and Wahl, S. (1994) Synthetic fibronectin peptides interrupt inflammatory cell infiltration in transforming growth factor f31 knockout mice. Proc. Natl. Acad. Sci. USA 91, 5187–5191.PubMedCrossRefGoogle Scholar
  48. 48.
    Diebold, R. J., Eis, M. J., Yin, M., Ormsby, I., Boivin, G. P., Darrow, B. J., Saffitz, J. E., and Doetschman T. (1995) Early-onset multifocal inflammation in the transforming growth factor 131- null mouse is lymphocyte mediated. Proc. Natl. Acad. Sci. USA 92, 12215–12219.PubMedCrossRefGoogle Scholar
  49. 49.
    Wahl, S. M. (1992) TGF-(3 in inflammation. A cause and a cure. J. Clin. Immunol. 12, 61–74.PubMedCrossRefGoogle Scholar
  50. 50.
    Tracey, K. J., Wei, H., Manogue, K. R., Fong, Y., Hesse, D. G., Nguyen, H. T., Kuo, G. C., Beutler, B., Cotran, R. S., Cerami, A., and Lowry, S. F. (1988) Cachectin/tumor necrosis factor induces cachexia, anemia, and inflammation. J. Exp. Med. 167, 1211–1227.PubMedCrossRefGoogle Scholar
  51. 51.
    Racke, M. K., Dhib-Jalbut, S., Cannella, B., Albert, P. S., Raine, C. S., and McFarlin, D. E. (1991) Prevention and treatment of chronic relapsing experimental allergic encephalomyelitis by transforming growth factor-131. J. Immunol. 146, 3012–3017.PubMedGoogle Scholar
  52. 52.
    Kuruvilla, A. P., Shah, R., Hochwald, G., M., Liggit, H. D., Palladino, M. A., and Thorbecke, G. J. (1991) Protective effect of transforming growth factor beta 1 on experimental autoimmune diseases in mice. Proc. Natl. Acad. Sci. USA 88, 2918–2921.Google Scholar
  53. 53.
    Khoury, S. J., Hancock, W. W., and Weiner, H. L. (1992) Oral tolerance to myelin basic protein and natural recovery from experimental autoimmune encephalomyelitis are associated with downregulation of inflammatory cytokines and differential upregulation of transforming growth factor beta, interleukin 4, and prostaglandin E expression in the brain. J. Exp. Med. 176, 1355–1364.CrossRefGoogle Scholar
  54. 54.
    Racke, M. K., Cannella, B., Albert, P., Sporn, M., Raine, C. S., and McFarlin, D. E. (1992) Evidence of endogenous regulatory function of transforming growth factor-(31 in experimental allergic encephalomyelitis. Intl. Immunol. 4, 615–620.CrossRefGoogle Scholar
  55. 55.
    Chen, Y., Kuchroo, V. K., Inobe, J., Hafler, D. A., and Weiner, H. L. (1994) Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. Science 265, 1237–1240.Google Scholar
  56. 56.
    Miller, A., Lider, O., Roberts, A. B., Sporn, M. B., and Weiner, H. L. (1992) Suppressor T-cells generated by oral tolerization to myelin basic protein suppress both in vitro and in vivo immune responses by the release of transforming growth factor (3 after antigen-specific triggering. Proc. Natl. Acad. Sci. USA 89, 421–425.PubMedCrossRefGoogle Scholar
  57. 57.
    Lowrance, J. H., O’Sullivan, F. X., Caver, T. E., Waegell, W., and Gresham, H. D. (1994) Spontaneous elaboration of transforming growth factor f3 suppresses host defense against bacterial infection in autoimmune MRL/lpr Mice. J. Exp. Med. 180, 1693–1703.PubMedCrossRefGoogle Scholar
  58. 58.
    McCartney-Francis, N. L., Mizel, D. E., Redman, R. S., Frazier-Jessen, M. R., Panek, R. B., Kulkarni, A. B., Ward, J. M., McCarthy, J. B., and Wahl, S. M. (1996) Autoimmune Sjögren’s-like lesions in salivary glands of TGF(31 deficient mice are inhibited by adhesion-blocking peptides. J. Immunol. 157, 1306–1312.PubMedGoogle Scholar
  59. 59.
    Dang, H., Geiser, A. G., Letterio, J. J., Nakabayashi, T., Kong, L., Fernandes, G., and Talal, N. (1995) SLE-like autoantibodies and Sjögren’s syndrome-like lymphoproliferation in TGF-131 knockout mice. J. Immunol. 155, 3205–3212.PubMedGoogle Scholar
  60. 60.
    Yaswen, L., Kulkarni, A., Frederickson, T., Mittleman, B., Schiffmann, R., Payne, S., Longenecker, G., Mozes, E., and Karlsson, S. (1995) Autoimmune manifestations in the TGF-131 knockout mouse. Blood 87, 1439–1445.Google Scholar
  61. 61.
    Hayakawa, K., Tarlinton, D., and Hardy, R. R. (1994) Absence of MHC class II expression distinguishes fetal from adult B-lymphopoiesis in mice. J. Immunol. 152, 4801–4807.PubMedGoogle Scholar
  62. 62.
    Velardi, A. and Cooper, M. D. (1984) An immunofluorescence analysis of the ontogeny of myeloid, T-, and B-lineage cells in mouse hemopoietic tissues. J. Immunol. 133, 672–677.PubMedGoogle Scholar
  63. 63.
    Scott, D. W. (1994) The Nature of Immunologic Tolerance. Landes, Austin, TX, pp. 15–98.Google Scholar
  64. 64.
    Christ, M., McCartney-Francis, N. L., Kulkarni, A. B., Ward, J. M., Mizel, D. E., Mackall, C. L., Gress, R. E., Hines, K. L., Tian, H., Karlsson, S., and Wahl, S. M. (1994) Immune dysregulation in TGF-(31-deficient mice. J. Immunol. 153, 1936–1946.PubMedGoogle Scholar
  65. 65.
    Geiser, A. G., Letterio, J. J., Kulkarni, A. B., Karlsson, S., Roberts, A. B., and Sporn, A. B. (1993) Transforming growth factor 131 (TGF-(31) controls expression of major histocompatibility genes in the postnatal mouse: Aberrant histocompatibility antigen expression in the pathogenesis of the TGF-(31 null mouse phenotype. Proc. Natl. Acad. Sci. USA 90, 9944–9948.PubMedCrossRefGoogle Scholar
  66. 66.
    Pujol-Borrell, R., Todd, I., Londei, M., Foulis, A., Feldmann, M., and Bottazzo, G. F. (1986) Inappropriate major histocompatibility complex class II expression by thyroid follicular cells in throid autoimmune disease, and by pancreatic beta cells in type I diabetes. Mol. Biol. Med. 3, 159–165.PubMedGoogle Scholar
  67. 67.
    Schwartz, R. S. and D. S. K. (1989) Autoimmunity and autoimmune disease, in Fundamental Immunology ( Paul, W. E., ed.) Raven. New York, pp. 819–866.Google Scholar
  68. 68.
    Steinman, L. (1995) Escape from “Horror Autotoxicus”: pathogenesis and treatment of autoimmune disease. Cell 80, 7–10.PubMedCrossRefGoogle Scholar
  69. 69.
    Reimold, A. M., Kara, C. J., Rooney, J. W., and Glimcher, L. H. (1993) Transforming growth factor (31 repression of the HLA-DRa gene is mediated by conserved proximal promoter elements. J. Immunol. 151, 4173–4182.PubMedGoogle Scholar
  70. 70.
    Czarniecki, C. W., Chiu, H. H., Wong, G. H., McCabe, S. M., and Palladino, M. A. (1988) Transforming growth factor-131 modulates the expression of class II histocompatibility antigens on human cells. J. Immunol. 140, 4217–4223.PubMedGoogle Scholar
  71. 71.
    Devajyothi, C., Kalvakolanu, I., Babcock, G. T., Vasavada, H. A., Howe, P. H., and Ransohoff, R. M. (1993) Inhibition of interferon-y-induced major histocompatibility complex class II gene transcription by interferon-(3 and type (31 transforming growth factor in human astrocytoma cells. J. Biol. Chem. 268, 18794–18800.PubMedGoogle Scholar
  72. 72.
    Schleusener, H. J. (1990) Transforming growth factors type beta 1 and beta 2 suppress rat astrocyte autoantigen presentation and antagonize hyperinduction of class U major histocompatibility complex antigen expression by interferon-gamma and tumor necrosis factor-alpha. J. Neuroimmunol. 27, 41–47.CrossRefGoogle Scholar
  73. 73.
    Sobel, R. A., Blanchette, B. W., Bhan, A. K., and Colvin, R. B. (1984) The immunopathology of acute experimental allergic encephalomyelitis. II. Endothelial cell Ia expression increases prior to inflammatory cell infiltration. J. Immunol. 132, 2402–2407.PubMedGoogle Scholar
  74. 73a.
    Letterio, J. J., Geiser, A. G., Kulkarni, A. B., Dang, H., Kong, L., Nakabayashi, T., Mackall, C. L., Gress, R. E., and Roberts, A. B. (1996) Autoimmunity associated with TGF-131 deficiency in mice is dependent on MHC class II antigen expression. J. Clin. Invest. 98, 2109–2119.PubMedCrossRefGoogle Scholar
  75. 74.
    Kappler, J. W., Roehm, N., and Marrack, P. (1987) T-cell tolerance by clonal elimination in the thymus. Cell 49, 273–280.PubMedCrossRefGoogle Scholar
  76. 75.
    McDuffie, M., Roehm, N., Kappler, J. W., and Marrack, P. (1988) Involvement of major histocompatibility complex products in tolerance induction in the thymus. J. Immunol. 141, 1840–1847.PubMedGoogle Scholar
  77. 76.
    Takahama, Y., Shores, E. W., and Singer, A. (1992) Negative selection of precursor thymocytes before their differentiation into CD4+CD8+ cells. Science 258, 653–656.PubMedCrossRefGoogle Scholar
  78. 77.
    Fowell, D. and Mason, D. (1993) Evidence that the T-cell repertoire of normal rats contains cells with the potential to cause diabetes. Characterization of the CD4+ T-cell subset that inhibits this autoimmune potential. J. Exp. Med. 177, 627–636.PubMedCrossRefGoogle Scholar
  79. 78.
    Powrie, F., Leach, M. W., Mauze, S., Menon, S., Caddie, L. B., and Coffman, R. L. (1994) Inhibition of Th1 responses prevents inflammatory bowel disease in scid mice reconstituted with CD45RBhi CD4+ T-Cells. Immunity 1, 553–562.PubMedCrossRefGoogle Scholar
  80. 79.
    Swain, S. L., Huston, G., Tonkonogy, S., and Weinberg, A. (1991) Transforming growth factor-beta and 1L4 cause helper T-cell precursors to develop into distinct effector helper T-cells that differ in lymphokine secretion pattern and cell surface phenotype. J. Immunol. 147, 2991–3000.PubMedGoogle Scholar
  81. 80.
    Smeland, E. B., Blomhoff, H. K., Holte, H., Ruud, E., Beiske, K., Funderud, S., Godal, T., and Ohlsson, R. (1987) Transforming growth factor(3 (TGF-(3) inhibits GI to S transition, but not activation of human B-lymphocytes. Exp. Cell Res. 171, 213–222.PubMedCrossRefGoogle Scholar
  82. 81.
    Kehrl, J. H., Roberts, A. B., Wakefield, R. M., Jakowlew, S., Sporn, M. B., and Fauci, A. S. (1986) Transforming Growth Factor (3 is an important immunomodulary protein for human B-lymphocytes. J. Immunol. 137, 3855–3860.PubMedGoogle Scholar
  83. 82.
    Flescher, E., Fossum, D., Ballester, A., Maizel, A., Sharma, S., and Talal, N. (1990) Characterization of B-cell growth in systemic lupus erythematosus: effects of recombinant 12kDa B-cell growth factor, interleukin-4, and transforming growth factor-(3. Eur. J. Immunol. 20, 2425–2430.PubMedCrossRefGoogle Scholar
  84. 83.
    Rehman, J. A. and LeBien, T. W., (1993) Transforming growth factor-(3 regulates normal human pre-B-cell differentiation. Int. Immunol. 6, 315–322.CrossRefGoogle Scholar
  85. 84.
    Heine, U., Munoz, E. F., Flanders, K. C., Ellingsworth, L. R., Lam, H. Y., Thompson, N. L., Roberts, A. B., and Sporn, M. B. (1987) Role of transforming growth factor (3 in the development of the mouse embryo. J. Cell Biol. 105, 2861–2876.PubMedCrossRefGoogle Scholar
  86. 85.
    Dickson, M. C., Martin, J. S., Cousins, F. M., Kulkarni, A. B., Karlsson, S., and Akhurst, R. J. (1995) Defective haematopoiesis and vasculogenesis in transforming growth factor-f31 knock out mice. Development 121, 1845–1854.PubMedGoogle Scholar
  87. 86.
    Letterio, J. J., Geiser, A. G., Kulkarni, A. B., Roche, N. S., Sporn, M. B., and Roberts, A. B. (1994) Maternal rescue of transforming growth factor-ß1 null mice. Science 264, 1936–1938.PubMedCrossRefGoogle Scholar
  88. 87.
    Shimamura, M., Ohta, S., Suzuki, R., and Yamazaki, K. (1994) Transmission of maternal blood cells to the fetus during pregnancy: detection in mouse neonatal spleen by inmiunofluorescence flow cytometry and polymerase chain reaction. Blood 83, 926–930.PubMedGoogle Scholar
  89. 88.
    Seelig, J. L. L. and Head, J. R. (1987) Uptake of lymphocytes fed to suckling rats. An autoradiographic study of the transit of labeled cells through the neonatal gastric mucosa. J. Rep rod. Immunol. 10, 285–297.CrossRefGoogle Scholar
  90. 89.
    Wakefield, L. M., Letterio, J. J., Chen, T., Danielpour, D., Allison, R., Pai, L. H., Denicoff, A. M., Noone, M. H., Cowan, K. H., O’Shaughnessy, J. A., and Sporn, M. B. (1995) Transforming growth factor-131 circulates in normal human plasma and is unchanged in advanced metastatic breast cancer. Clin. Cancer Res. 1, 129–136.PubMedGoogle Scholar
  91. 90.
    Anscher, M. S., Peters, W. P., Reisenbichler, H., Petros, W. P., and Jirtle, R. L. (1993) Transforming growth factor-(3 as a predictor of liver and lung fibrosis after autologous bone marrow transplantation for advanced breast cancer. N. Engl. Med. 328, 1592–1598.CrossRefGoogle Scholar
  92. 91.
    Ivanovic, V., Melman, A., Davis-Joseph, B., Valcic, M., and Geliebter, J. (1995) Elevated plasma levels of TGF-131 in patients with invasive prostate cancer. Nature Med. 1, 282–283.PubMedCrossRefGoogle Scholar
  93. 92.
    Grainger, D. J., Kemp, P. R., Metcalfe, J. C., Liu, A. C., Lawn, R. M., Williams, N. R., Grace, A. A., Schofield, P. M., and Chauhan, A. (1995) The serum concentration of active transforming growth factor-(3 is severely depressed in advanced atherosclerosis. Nature Med. 1, 74–79.PubMedCrossRefGoogle Scholar
  94. 93.
    Allen, J. B., Wong, H. L., Guyre, P. M., Simon, G. L., and Wahl, S. M. (1991) Association of circulating Fc gamma RITI-positive monocytes in AIDS patients with elevated levels of transforming growth factor -beta. J. Clin. Invest. 87, 1773–1779.PubMedCrossRefGoogle Scholar
  95. 94.
    Stach, R. M. and Rowley, D. A. (1993) A first or dominant immunization. II. Induced immunoglobulin carries transforming growth factor beta and suppresses cytolytic T-cell responses to unrelated alloantigens. J. Exp. Med. 178, 841–852.PubMedCrossRefGoogle Scholar
  96. 95.
    Longaker, M. T., Bouhana, K. S., Harrison, M. R., Danielpour, D., Roberts, A. B., and Banda, M. J. (1994) Wound Healing in the fetus: possible role for inflammatory macrophages and transforming growth factor-13 isoforms. Wound Rep. Reg. 2, 104–112.CrossRefGoogle Scholar
  97. 96.
    Brown, R. L., Ormsby, I., Doetschman, T. C., and Greenhalgh, D. G. (1995) Wound healing in the transforming growth factor431- deficient mouse. Wound Rep. Reg. 3, 25–36.CrossRefGoogle Scholar
  98. 97.
    Shah, M., Foreman, D. M., and Ferguson, W. J. (1995) Neutralization of TGF-131 and TGF-132 or exogenous addition of TGF-133 to cutaneous rat wounds reduces scarring. J. Cell Sci. 108, 985–1002.PubMedGoogle Scholar
  99. 98.
    Hannon, G. J. and Beach, D. (1994) p15INK4B is a potential effector of TGF-13-induced cell cycle arrest. Nature 371, 257–261.Google Scholar
  100. 99.
    Datto, M. B., Li, Y., Panus, J. F., Howe, D. J., Xiong, Y., and Wang, X. F. (1995) Transforming growth factor (3 induces the cyclin-dependent kinase inhibitor p21 through a p53-independent mechanism. Proc. Natl. Acad. Sci. USA 92, 5545–5549.PubMedCrossRefGoogle Scholar
  101. 100.
    Li, C. Y., Suardet, L., and Little, J. B. (1995) Potential role of WAF1/Cipl/p21 as a mediator of TGF-13 cytoinhibitory effect. J. Biol. Chem. 270, 4971–4974.PubMedCrossRefGoogle Scholar
  102. 101.
    Ewen, M. E., Sluss, H. K., Whitehouse, L. L., and Livingston, D. M. (1993) TGF-(3 inhibition of Cdk4 synthesis is linked to cell cycle arrest. Cell 74, 1009–1020.PubMedCrossRefGoogle Scholar
  103. 102.
    Toyoshima, H. and Hunter, T. (1994) p27, a novel inhibitor of G1 cyclinCdk protein kinase activity, is related to p21. Cell 78, 67–74.Google Scholar
  104. 103.
    Glick, A. B., Kulkarni, A. B., Tennenbaum, T., Hennings, H., Flanders, K. C., O’Reilly, M., Sporn, M. B., Karlsson, S., and Yuspa, S. H. (1993) Loss of expression of transforming growth factor in skin and skin tumors is associated with hyperproliferation and a high risk for malignant conversion. Proc. Natl. Acad. Sci. USA 90, 6076–6080.PubMedCrossRefGoogle Scholar
  105. 104.
    Glick, A. B., Lee, M. M., Darwiche, N., Kulkarni, A. B. Karlsson, S., and Yuspa, S. H. (1994) Targeted deletion of the TGF-31 gene causes rapid progression to squamous cell carcinoma. Genes Dey. 8, 2429–2440.Google Scholar
  106. 105.
    Akhurst, R. J., Fee, F., and Balmain, A. (1988) Localized production of TGF-beta mRNA in tumor promoter-stimulated mouse epidermis. Nature 331, 363–365.PubMedCrossRefGoogle Scholar
  107. 106.
    Fowlis, D. J., Flanders, K. C., Duffie, E., Balmain, A., and Akhurst, R. J. (1992) Discordant transforming growth factor 131 RNA and protein localization during chemical carcinogenesis of the skin. Cell Growth Differ. 3, 81–91.PubMedGoogle Scholar
  108. 107.
    Glick, A. B., Lee, M. M., Wu, I. H., Catalano, C., Weinberg, W., and Yuspa, S. H. (1995) Genomic Instability in cell lines derived from TGF-(31 null keratinocytes. Proc. 86th Ann. Meeting Am. Assoc. Cancer Res. 36, 544.Google Scholar
  109. 108.
    Park, K., Kim, S. J., Bang, Y. J., Park, J. G., Kim, N. K., Roberts, A. B., and Sporn, M. B. (1994) Genetic changes in the transforming growth factor ß (TGF-0) type II receptor gene in human gastric cancer cells: correlation with sensitivity to growth inhibition by TGF-(3. Proc. Natl. Acad. Sci. USA 91, 8772–8776.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1998

Authors and Affiliations

  • Ashok B. Kulkarni
  • John J. Letterio

There are no affiliations available

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