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. 1993 Jan 15;90(2):770–774. doi: 10.1073/pnas.90.2.770

Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death.

A B Kulkarni 1, C G Huh 1, D Becker 1, A Geiser 1, M Lyght 1, K C Flanders 1, A B Roberts 1, M B Sporn 1, J M Ward 1, S Karlsson 1
PMCID: PMC45747  PMID: 8421714

Abstract

To delineate specific developmental roles of transforming growth factor beta 1 (TGF-beta 1) we have disrupted its cognate gene in mouse embryonic stem cells by homologous recombination to generate TGF-beta 1 null mice. These mice do not produce detectable amounts of either TGF-beta 1 RNA or protein. After normal growth for the first 2 weeks they develop a rapid wasting syndrome and die by 3-4 weeks of age. Pathological examination revealed an excessive inflammatory response with massive infiltration of lymphocytes and macrophages in many organs, but primarily in heart and lungs. Many lesions resembled those found in autoimmune disorders, graft-vs.-host disease, or certain viral diseases. This phenotype suggests a prominent role for TGF-beta 1 in homeostatic regulation of immune cell proliferation and extravasation into tissues.

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Selected References

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

  1. Bartlett W. C., Purchio A., Fell H. P., Noelle R. J. Cognate interactions between helper T cells and B cells. VI. TGF-beta inhibits B cell activation and antigen-specific, physical interactions between Th and B cells. Lymphokine Cytokine Res. 1991 Jun;10(3):177–183. [PubMed] [Google Scholar]
  2. Capecchi M. R. Altering the genome by homologous recombination. Science. 1989 Jun 16;244(4910):1288–1292. doi: 10.1126/science.2660260. [DOI] [PubMed] [Google Scholar]
  3. Cherayil B. J., Weiner S. J., Pillai S. The Mac-2 antigen is a galactose-specific lectin that binds IgE. J Exp Med. 1989 Dec 1;170(6):1959–1972. doi: 10.1084/jem.170.6.1959. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. 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]
  5. Flanders K. C., Thompson N. L., Cissel D. S., Van Obberghen-Schilling E., Baker C. C., Kass M. E., Ellingsworth L. R., Roberts A. B., Sporn M. B. Transforming growth factor-beta 1: histochemical localization with antibodies to different epitopes. J Cell Biol. 1989 Feb;108(2):653–660. doi: 10.1083/jcb.108.2.653. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Gamble J. R., Vadas M. A. Endothelial adhesiveness for blood neutrophils is inhibited by transforming growth factor-beta. Science. 1988 Oct 7;242(4875):97–99. doi: 10.1126/science.3175638. [DOI] [PubMed] [Google Scholar]
  7. Gamble J. R., Vadas M. A. Endothelial cell adhesiveness for human T lymphocytes is inhibited by transforming growth factor-beta 1. J Immunol. 1991 Feb 15;146(4):1149–1154. [PubMed] [Google Scholar]
  8. Geiser A. G., Kim S. J., Roberts A. B., Sporn M. B. Characterization of the mouse transforming growth factor-beta 1 promoter and activation by the Ha-ras oncogene. Mol Cell Biol. 1991 Jan;11(1):84–92. doi: 10.1128/mcb.11.1.84. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Goey H., Keller J. R., Back T., Longo D. L., Ruscetti F. W., Wiltrout R. H. Inhibition of early murine hemopoietic progenitor cell proliferation after in vivo locoregional administration of transforming growth factor-beta 1. J Immunol. 1989 Aug 1;143(3):877–880. [PubMed] [Google Scholar]
  10. Gresham H. D., Ray C. J., O'Sullivan F. X. Defective neutrophil function in the autoimmune mouse strain MRL/lpr. Potential role of transforming growth factor-beta. J Immunol. 1991 Jun 1;146(11):3911–3921. [PubMed] [Google Scholar]
  11. Hart M. N., Sadewasser K. L., Cancilla P. A., DeBault L. E. Experimental autoimmune type of vasculitis resulting from activation of mouse lymphocytes to cultured endothelium. Lab Invest. 1983 Apr;48(4):419–427. [PubMed] [Google Scholar]
  12. Johns L. D., Flanders K. C., Ranges G. E., Sriram S. Successful treatment of experimental allergic encephalomyelitis with transforming growth factor-beta 1. J Immunol. 1991 Sep 15;147(6):1792–1796. [PubMed] [Google Scholar]
  13. Keller J. R., Sing G. K., Ellingsworth L. R., Ruscetti S. K., Ruscetti F. W. Two forms of transforming growth factor-beta are equally potent selective growth inhibitors of early murine hematopoiesis. Ann N Y Acad Sci. 1990;593:172–180. doi: 10.1111/j.1749-6632.1990.tb16109.x. [DOI] [PubMed] [Google Scholar]
  14. Lucas C., Wallick S., Fendly B. M., Figari I., Palladino M. A. TGF-beta: a possible autocrine immune regulator. Ciba Found Symp. 1991;157:98–114. doi: 10.1002/9780470514061.ch7. [DOI] [PubMed] [Google Scholar]
  15. Mansour S. L., Thomas K. R., Capecchi M. R. Disruption of the proto-oncogene int-2 in mouse embryo-derived stem cells: a general strategy for targeting mutations to non-selectable genes. Nature. 1988 Nov 24;336(6197):348–352. doi: 10.1038/336348a0. [DOI] [PubMed] [Google Scholar]
  16. Massagué J. The transforming growth factor-beta family. Annu Rev Cell Biol. 1990;6:597–641. doi: 10.1146/annurev.cb.06.110190.003121. [DOI] [PubMed] [Google Scholar]
  17. McBurney M. W., Sutherland L. C., Adra C. N., Leclair B., Rudnicki M. A., Jardine K. The mouse Pgk-1 gene promoter contains an upstream activator sequence. Nucleic Acids Res. 1991 Oct 25;19(20):5755–5761. doi: 10.1093/nar/19.20.5755. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Miller A., Lider O., Roberts A. B., Sporn M. B., Weiner H. L. 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 beta after antigen-specific triggering. Proc Natl Acad Sci U S A. 1992 Jan 1;89(1):421–425. doi: 10.1073/pnas.89.1.421. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. 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]
  20. Paria B. C., Jones K. L., Flanders K. C., Dey S. K. Localization and binding of transforming growth factor-beta isoforms in mouse preimplantation embryos and in delayed and activated blastocysts. Dev Biol. 1992 May;151(1):91–104. doi: 10.1016/0012-1606(92)90216-4. [DOI] [PubMed] [Google Scholar]
  21. Racke M. K., Cannella B., Albert P., Sporn M., Raine C. S., McFarlin D. E. Evidence of endogenous regulatory function of transforming growth factor-beta 1 in experimental allergic encephalomyelitis. Int Immunol. 1992 May;4(5):615–620. doi: 10.1093/intimm/4.5.615. [DOI] [PubMed] [Google Scholar]
  22. Rappaport H., Khalil A., Halle-Pannenko O., Pritchard L., Dantchev D., Mathé G. Histopathologic sequence of events in adult mice undergoing lethal graft-versus-host reaction developed across H-2 and/or non-H-2 histocompatibility barriers. Am J Pathol. 1979 Jul;96(1):121–142. [PMC free article] [PubMed] [Google Scholar]
  23. Rappolee D. A., Brenner C. A., Schultz R., Mark D., Werb Z. Developmental expression of PDGF, TGF-alpha, and TGF-beta genes in preimplantation mouse embryos. Science. 1988 Sep 30;241(4874):1823–1825. doi: 10.1126/science.3175624. [DOI] [PubMed] [Google Scholar]
  24. Robertson E. J. Using embryonic stem cells to introduce mutations into the mouse germ line. Biol Reprod. 1991 Feb;44(2):238–245. doi: 10.1095/biolreprod44.2.238. [DOI] [PubMed] [Google Scholar]
  25. Saiki R. K., Scharf S., Faloona F., Mullis K. B., Horn G. T., Erlich H. A., Arnheim N. Enzymatic amplification of beta-globin genomic sequences and restriction site analysis for diagnosis of sickle cell anemia. Science. 1985 Dec 20;230(4732):1350–1354. doi: 10.1126/science.2999980. [DOI] [PubMed] [Google Scholar]
  26. Shull M. M., Ormsby I., Kier A. B., Pawlowski S., Diebold R. J., Yin M., Allen R., Sidman C., Proetzel G., Calvin D. Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature. 1992 Oct 22;359(6397):693–699. doi: 10.1038/359693a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Staszak C., Harbeck R. J. Mononuclear-cell pulmonary vasculitis in NZB/W mice. I. Histopathologic evaluation of spontaneously occurring pulmonary infiltrates. Am J Pathol. 1985 Jul;120(1):99–105. [PMC free article] [PubMed] [Google Scholar]
  28. Tamada H., McMaster M. T., Flanders K. C., Andrews G. K., Dey S. K. Cell type-specific expression of transforming growth factor-beta 1 in the mouse uterus during the periimplantation period. Mol Endocrinol. 1990 Jul;4(7):965–972. doi: 10.1210/mend-4-7-965. [DOI] [PubMed] [Google Scholar]
  29. Tindall K. R., Stankowski L. F., Jr Molecular analysis of spontaneous mutations at the gpt locus in Chinese hamster ovary (AS52) cells. Mutat Res. 1989 Mar-May;220(2-3):241–253. doi: 10.1016/0165-1110(89)90028-6. [DOI] [PubMed] [Google Scholar]
  30. Wahl S. M. Transforming growth factor beta (TGF-beta) in inflammation: a cause and a cure. J Clin Immunol. 1992 Mar;12(2):61–74. doi: 10.1007/BF00918135. [DOI] [PubMed] [Google Scholar]
  31. 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]

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