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. 1990 Dec 1;172(6):1777–1784. doi: 10.1084/jem.172.6.1777

Immunoregulatory role of transforming growth factor beta (TGF-beta) in development of killer cells: comparison of active and latent TGF-beta 1

PMCID: PMC2188774  PMID: 2258706

Abstract

Using recombinant DNA technology, we have generated Chinese hamster ovary (CHO) cell lines that synthesize latent transforming growth factor beta 1 (TGF-beta 1) to study immune regulation by TGF-beta 1. In vitro, latent TGF-beta 1 synthesized by transfectants or added exogenously as a purified complex after activation inhibited CTL generation to a similar extent as seen with acid-activated recombinant human (rHu) TGF-beta 1. In vivo, serum from nu/nu mice bearing CHO/TGF- beta 1 tumors contained significant levels of latent TGF-beta 1 in addition to depressed natural killer (NK) activity in spleens which paralleled that seen in C3H/HeJ mice treated with acid-activated rHuTGF- beta 1. rHuTGF-beta 1 treatment of mice receiving heart allografts resulted in significant enhancement of organ graft survival. Because of possible regulated tissue-specific activation, administration of latent rather than active TGF-beta may provide a better route to deliver this powerful immunosuppressive agent in vivo.

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Selected References

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  1. Antonelli-Orlidge A., Saunders K. B., Smith S. R., D'Amore P. A. An activated form of transforming growth factor beta is produced by cocultures of endothelial cells and pericytes. Proc Natl Acad Sci U S A. 1989 Jun;86(12):4544–4548. doi: 10.1073/pnas.86.12.4544. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Arrick B. A., Korc M., Derynck R. Differential regulation of expression of three transforming growth factor beta species in human breast cancer cell lines by estradiol. Cancer Res. 1990 Jan 15;50(2):299–303. [PubMed] [Google Scholar]
  3. Assoian R. K., Fleurdelys B. E., Stevenson H. C., Miller P. J., Madtes D. K., Raines E. W., Ross R., Sporn M. B. Expression and secretion of type beta transforming growth factor by activated human macrophages. Proc Natl Acad Sci U S A. 1987 Sep;84(17):6020–6024. doi: 10.1073/pnas.84.17.6020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bodmer S., Strommer K., Frei K., Siepl C., de Tribolet N., Heid I., Fontana A. Immunosuppression and transforming growth factor-beta in glioblastoma. Preferential production of transforming growth factor-beta 2. J Immunol. 1989 Nov 15;143(10):3222–3229. [PubMed] [Google Scholar]
  5. Chantry D., Turner M., Feldmann M. Interleukin 7 (murine pre-B cell growth factor/lymphopoietin 1) stimulates thymocyte growth: regulation by transforming growth factor beta. Eur J Immunol. 1989 Apr;19(4):783–786. doi: 10.1002/eji.1830190433. [DOI] [PubMed] [Google Scholar]
  6. Coffman R. L., Lebman D. A., Shrader B. Transforming growth factor beta specifically enhances IgA production by lipopolysaccharide-stimulated murine B lymphocytes. J Exp Med. 1989 Sep 1;170(3):1039–1044. doi: 10.1084/jem.170.3.1039. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Czarniecki C. W., Chiu H. H., Wong G. H., McCabe S. M., Palladino M. A. Transforming growth factor-beta 1 modulates the expression of class II histocompatibility antigens on human cells. J Immunol. 1988 Jun 15;140(12):4217–4223. [PubMed] [Google Scholar]
  8. Danielpour D., Dart L. L., Flanders K. C., Roberts A. B., Sporn M. B. Immunodetection and quantitation of the two forms of transforming growth factor-beta (TGF-beta 1 and TGF-beta 2) secreted by cells in culture. J Cell Physiol. 1989 Jan;138(1):79–86. doi: 10.1002/jcp.1041380112. [DOI] [PubMed] [Google Scholar]
  9. Derynck R., Jarrett J. A., Chen E. Y., Eaton D. H., Bell J. R., Assoian R. K., Roberts A. B., Sporn M. B., Goeddel D. V. Human transforming growth factor-beta complementary DNA sequence and expression in normal and transformed cells. Nature. 1985 Aug 22;316(6030):701–705. doi: 10.1038/316701a0. [DOI] [PubMed] [Google Scholar]
  10. Espevik T., Figari I. S., Ranges G. E., Palladino M. A., Jr Transforming growth factor-beta 1 (TGF-beta 1) and recombinant human tumor necrosis factor-alpha reciprocally regulate the generation of lymphokine-activated killer cell activity. Comparison between natural porcine platelet-derived TGF-beta 1 and TGF-beta 2, and recombinant human TGF-beta 1. J Immunol. 1988 Apr 1;140(7):2312–2316. [PubMed] [Google Scholar]
  11. Espevik T., Figari I. S., Shalaby M. R., Lackides G. A., Lewis G. D., Shepard H. M., Palladino M. A., Jr Inhibition of cytokine production by cyclosporin A and transforming growth factor beta. J Exp Med. 1987 Aug 1;166(2):571–576. doi: 10.1084/jem.166.2.571. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Fontana A., Frei K., Bodmer S., Hofer E., Schreier M. H., Palladino M. A., Jr, Zinkernagel R. M. Transforming growth factor-beta inhibits the generation of cytotoxic T cells in virus-infected mice. J Immunol. 1989 Nov 15;143(10):3230–3234. [PubMed] [Google Scholar]
  13. Gentry L. E., Lioubin M. N., Purchio A. F., Marquardt H. Molecular events in the processing of recombinant type 1 pre-pro-transforming growth factor beta to the mature polypeptide. Mol Cell Biol. 1988 Oct;8(10):4162–4168. doi: 10.1128/mcb.8.10.4162. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Jullien P., Berg T. M., Lawrence D. A. Acidic cellular environments: activation of latent TGF-beta and sensitization of cellular responses to TGF-beta and EGF. Int J Cancer. 1989 May 15;43(5):886–891. doi: 10.1002/ijc.2910430525. [DOI] [PubMed] [Google Scholar]
  15. Kehrl J. H., Roberts A. B., Wakefield L. M., Jakowlew S., Sporn M. B., Fauci A. S. Transforming growth factor beta is an important immunomodulatory protein for human B lymphocytes. J Immunol. 1986 Dec 15;137(12):3855–3860. [PubMed] [Google Scholar]
  16. Kehrl J. H., Taylor A. S., Delsing G. A., Roberts A. B., Sporn M. B., Fauci A. S. Further studies of the role of transforming growth factor-beta in human B cell function. J Immunol. 1989 Sep 15;143(6):1868–1874. [PubMed] [Google Scholar]
  17. Kehrl J. H., Wakefield L. M., Roberts A. B., Jakowlew S., Alvarez-Mon M., Derynck R., Sporn M. B., Fauci A. S. Production of transforming growth factor beta by human T lymphocytes and its potential role in the regulation of T cell growth. J Exp Med. 1986 May 1;163(5):1037–1050. doi: 10.1084/jem.163.5.1037. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Knabbe C., Lippman M. E., Wakefield L. M., Flanders K. C., Kasid A., Derynck R., Dickson R. B. Evidence that transforming growth factor-beta is a hormonally regulated negative growth factor in human breast cancer cells. Cell. 1987 Feb 13;48(3):417–428. doi: 10.1016/0092-8674(87)90193-0. [DOI] [PubMed] [Google Scholar]
  19. Lawrence D. A., Pircher R., Jullien P. Conversion of a high molecular weight latent beta-TGF from chicken embryo fibroblasts into a low molecular weight active beta-TGF under acidic conditions. Biochem Biophys Res Commun. 1985 Dec 31;133(3):1026–1034. doi: 10.1016/0006-291x(85)91239-2. [DOI] [PubMed] [Google Scholar]
  20. Lucas C., Bald L. N., Fendly B. M., Mora-Worms M., Figari I. S., Patzer E. J., Palladino M. A. The autocrine production of transforming growth factor-beta 1 during lymphocyte activation. A study with a monoclonal antibody-based ELISA. J Immunol. 1990 Sep 1;145(5):1415–1422. [PubMed] [Google Scholar]
  21. Lyons R. M., Keski-Oja J., Moses H. L. Proteolytic activation of latent transforming growth factor-beta from fibroblast-conditioned medium. J Cell Biol. 1988 May;106(5):1659–1665. doi: 10.1083/jcb.106.5.1659. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Miescher S., Whiteside T. L., Carrel S., von Fliedner V. Functional properties of tumor-infiltrating and blood lymphocytes in patients with solid tumors: effects of tumor cells and their supernatants on proliferative responses of lymphocytes. J Immunol. 1986 Mar 1;136(5):1899–1907. [PubMed] [Google Scholar]
  23. Miyazono K., Heldin C. H. Role for carbohydrate structures in TGF-beta 1 latency. Nature. 1989 Mar 9;338(6211):158–160. doi: 10.1038/338158a0. [DOI] [PubMed] [Google Scholar]
  24. Miyazono K., Hellman U., Wernstedt C., Heldin C. H. Latent high molecular weight complex of transforming growth factor beta 1. Purification from human platelets and structural characterization. J Biol Chem. 1988 May 5;263(13):6407–6415. [PubMed] [Google Scholar]
  25. O'Connor-McCourt M. D., Wakefield L. M. Latent transforming growth factor-beta in serum. A specific complex with alpha 2-macroglobulin. J Biol Chem. 1987 Oct 15;262(29):14090–14099. [PubMed] [Google Scholar]
  26. Oreffo R. O., Mundy G. R., Seyedin S. M., Bonewald L. F. Activation of the bone-derived latent TGF beta complex by isolated osteoclasts. Biochem Biophys Res Commun. 1989 Feb 15;158(3):817–823. doi: 10.1016/0006-291x(89)92795-2. [DOI] [PubMed] [Google Scholar]
  27. Palladino M. A., Morris R. E., Starnes H. F., Levinson A. D. The transforming growth factor-betas. A new family of immunoregulatory molecules. Ann N Y Acad Sci. 1990;593:181–187. doi: 10.1111/j.1749-6632.1990.tb16110.x. [DOI] [PubMed] [Google Scholar]
  28. Pilatte Y., Bignon J., Lambré C. R. Lysosomal and cytosolic sialidases in rabbit alveolar macrophages: demonstration of increased lysosomal activity after in vivo activation with bacillus Calmette-Guerin. Biochim Biophys Acta. 1987 Jan 20;923(1):150–155. doi: 10.1016/0304-4165(87)90138-3. [DOI] [PubMed] [Google Scholar]
  29. Pircher R., Jullien P., Lawrence D. A. Beta-transforming growth factor is stored in human blood platelets as a latent high molecular weight complex. Biochem Biophys Res Commun. 1986 Apr 14;136(1):30–37. doi: 10.1016/0006-291x(86)90872-7. [DOI] [PubMed] [Google Scholar]
  30. Ranges G. E., Figari I. S., Espevik T., Palladino M. A., Jr Inhibition of cytotoxic T cell development by transforming growth factor beta and reversal by recombinant tumor necrosis factor alpha. J Exp Med. 1987 Oct 1;166(4):991–998. doi: 10.1084/jem.166.4.991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Roberts A. B., Anzano M. A., Wakefield L. M., Roche N. S., Stern D. F., Sporn M. B. Type beta transforming growth factor: a bifunctional regulator of cellular growth. Proc Natl Acad Sci U S A. 1985 Jan;82(1):119–123. doi: 10.1073/pnas.82.1.119. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Roberts A. B., Sporn M. B. Transforming growth factor beta. Adv Cancer Res. 1988;51:107–145. [PubMed] [Google Scholar]
  33. Rook A. H., Kehrl J. H., Wakefield L. M., Roberts A. B., Sporn M. B., Burlington D. B., Lane H. C., Fauci A. S. Effects of transforming growth factor beta on the functions of natural killer cells: depressed cytolytic activity and blunting of interferon responsiveness. J Immunol. 1986 May 15;136(10):3916–3920. [PubMed] [Google Scholar]
  34. Silver I. A., Murrills R. J., Etherington D. J. Microelectrode studies on the acid microenvironment beneath adherent macrophages and osteoclasts. Exp Cell Res. 1988 Apr;175(2):266–276. doi: 10.1016/0014-4827(88)90191-7. [DOI] [PubMed] [Google Scholar]
  35. Sonoda E., Matsumoto R., Hitoshi Y., Ishii T., Sugimoto M., Araki S., Tominaga A., Yamaguchi N., Takatsu K. Transforming growth factor beta induces IgA production and acts additively with interleukin 5 for IgA production. J Exp Med. 1989 Oct 1;170(4):1415–1420. doi: 10.1084/jem.170.4.1415. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Sporn M. B., Roberts A. B., Wakefield L. M., Assoian R. K. Transforming growth factor-beta: biological function and chemical structure. Science. 1986 Aug 1;233(4763):532–534. doi: 10.1126/science.3487831. [DOI] [PubMed] [Google Scholar]
  37. Tanaka M., Lee K. C., Yodoi J., Saito H., Iwai Y., Kim K. M., Morita M., Mayumi M., Mikawa H. Regulation of Fc epsilon receptor 2 (CD23) expression on a human eosinophilic cell line EoL3 and a human monocytic cell line U937 by transforming growth factor beta. Cell Immunol. 1989 Aug;122(1):96–107. doi: 10.1016/0008-8749(89)90151-2. [DOI] [PubMed] [Google Scholar]
  38. Torre-Amione G., Beauchamp R. D., Koeppen H., Park B. H., Schreiber H., Moses H. L., Rowley D. A. A highly immunogenic tumor transfected with a murine transforming growth factor type beta 1 cDNA escapes immune surveillance. Proc Natl Acad Sci U S A. 1990 Feb;87(4):1486–1490. doi: 10.1073/pnas.87.4.1486. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Tsunawaki S., Sporn M., Ding A., Nathan C. Deactivation of macrophages by transforming growth factor-beta. Nature. 1988 Jul 21;334(6179):260–262. doi: 10.1038/334260a0. [DOI] [PubMed] [Google Scholar]
  40. Urlaub G., Chasin L. A. Isolation of Chinese hamster cell mutants deficient in dihydrofolate reductase activity. Proc Natl Acad Sci U S A. 1980 Jul;77(7):4216–4220. doi: 10.1073/pnas.77.7.4216. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Wahl S. M., Hunt D. A., Wakefield L. M., McCartney-Francis N., Wahl L. M., Roberts A. B., Sporn M. B. Transforming growth factor type beta induces monocyte chemotaxis and growth factor production. Proc Natl Acad Sci U S A. 1987 Aug;84(16):5788–5792. doi: 10.1073/pnas.84.16.5788. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Wakefield L. M., Smith D. M., Broz S., Jackson M., Levinson A. D., Sporn M. B. Recombinant TGF-beta 1 is synthesized as a two-component latent complex that shares some structural features with the native platelet latent TGF-beta 1 complex. Growth Factors. 1989;1(3):203–218. doi: 10.3109/08977198908997997. [DOI] [PubMed] [Google Scholar]
  43. Wakefield L. M., Smith D. M., Flanders K. C., Sporn M. B. Latent transforming growth factor-beta from human platelets. A high molecular weight complex containing precursor sequences. J Biol Chem. 1988 Jun 5;263(16):7646–7654. [PubMed] [Google Scholar]
  44. Wakefield L. M., Smith D. M., Masui T., Harris C. C., Sporn M. B. Distribution and modulation of the cellular receptor for transforming growth factor-beta. J Cell Biol. 1987 Aug;105(2):965–975. doi: 10.1083/jcb.105.2.965. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Wiseman D. M., Polverini P. J., Kamp D. W., Leibovich S. J. Transforming growth factor-beta (TGF beta) is chemotactic for human monocytes and induces their expression of angiogenic activity. Biochem Biophys Res Commun. 1988 Dec 15;157(2):793–800. doi: 10.1016/s0006-291x(88)80319-x. [DOI] [PubMed] [Google Scholar]
  46. Wrann M., Bodmer S., de Martin R., Siepl C., Hofer-Warbinek R., Frei K., Hofer E., Fontana A. T cell suppressor factor from human glioblastoma cells is a 12.5-kd protein closely related to transforming growth factor-beta. EMBO J. 1987 Jun;6(6):1633–1636. doi: 10.1002/j.1460-2075.1987.tb02411.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Zuber P., Kuppner M. C., De Tribolet N. Transforming growth factor-beta 2 down-regulates HLA-DR antigen expression on human malignant glioma cells. Eur J Immunol. 1988 Oct;18(10):1623–1626. doi: 10.1002/eji.1830181023. [DOI] [PubMed] [Google Scholar]

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