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Novel Transforming Growth Factor Betas (TGFβ2) in Pregnancy and Cancer

  • David A. Clark
  • Kathleen C. Flanders
  • Gill Vince
  • Phyllis Starkey
  • Hal Hirte
  • Justin Manuel
  • Jennifer Underwood
  • James Mowbray
Part of the Serono Symposia, USA book series (SERONOSYMP)

Abstract

A number of cytokines may be present at the fetomaternal interface (1), and these may determine whether the implanted mammalian conceptus will succeed or fail. Certain cytokines have the potential to compromise the pregnancy and cause abortion:tumor necrosis factor α (TNFα), interleukin-1 (IL-1), and interferon γ (IFNγ). This may involve activation of natural killer (NK) lineage cells into lymphokine-activated killer (LAK) cells that have the capacity to damage fetal trophoblast cells (2–7) that lie at the fetomaternal interface and are crucial for placentation and embryo survival (8). Other cytokines have been postulated to be favorable to survival of the pregnancy. Three of these—interleukin-10 (IL-10), granulocyte-macrophage colony stimulating factor (GM-CSF), and transforming growth factor β (TGFβ)—appear to counter those cytokine-dependent processes that are antagonistic to pregnancy. IL-10 does not block generation of LAK cells in response to interleukin-2 (IL-2) (9–13), but can inhibit release of IL-2, TNFα, and related cytokines that are abortogenic. IL-10-deficient mice give birth to babies that are smaller than normal, but apparently do not have a higher resorption (abortion) rate (14). This may be due to the well-known phenomenon of redundancy, whereby several different cytokines produce the same effects, and this preserves a degree of protection when one cytokine is missing. GM-CSF, which is produced by fetal trophoblast (15, 16), has been shown to inhibit the generation of antitrophoblast LAK-like cells in vivo (17 and Clark, Chaouat, Mogil, Wegmann, manuscript submitted). Further, a potent immunosuppressive molecule closely related to TGFβ2 that blocks LAK generation and macrophage activation and cytokine release is also present at the fetomaternal interface (7, 18–20). These TGFβ2-like molecules appear to be released by bone marrow-derived natural suppressor cells and to have unusual molecular properties (20, 21).

Keywords

Transform Growth Factor Beta Suppressor Cell Suppressive Activity Pregnant Mouse Suppressor Cell Activity 
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.

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References

  1. 1.
    Clark DA. Cytokines, decidua and early pregnancy. In:Milligan SR, ed. Oxf Rev Reprod Biol 1993:83–111.Google Scholar
  2. 2.
    Chaoaut G, Menu E, Clark DA, Minkowsky M, Dy M, Wegmann TG. Control of fetal survival in CBA x DBA/2 mice by lymphokine therapy. J Reprod Fertil 1990;89:447–58.CrossRefGoogle Scholar
  3. 3.
    Gendron RL, Nestel FP, Lapp WS, Baines MG. Lipopolysaccharide-induced fetal resorption in mice is associated with the intrauterine production of tumour necrosis factor-alpha. J Reprod Fertil 1990;90:395–402.PubMedCrossRefGoogle Scholar
  4. 4.
    Silen M, Firpo A, Morgello S, Lowry SF, Francus T. Interleukin-1 alpha and tumor necrosis factor alpha cause placental injury in the rat. Am J Pathol 1989;135:239–44.PubMedGoogle Scholar
  5. 5.
    Ecker JL, Laufer MR, Hill JA. Measurement of embryotoxic factors is predictive of pregnancy outcome in women with a history of recurrent abortion. Obstet Gynecol 1993;81:1–4.Google Scholar
  6. 6.
    Clark DA. Controversies in reproductive immunology. Boca Raton, FL:CRC Press, 1991:215–47.Google Scholar
  7. 7.
    Clark DA, Lea RG, Flanders KC, Banwatt D, Chaoaut G. Role of a unique species of TGF-ßin preventing rejection of the conceptus during pregnancy. In:Gergely J, Benczúr M, Erdei N, et al., eds. Progress in immunology VIII. Budapest:Springer-Verlag, 1992:841–7.Google Scholar
  8. 8.
    Rossant J, Mauro VM, Croy BA. Importance of trophoblast genotype for survival of interspecific murine chimeras. J Embryol Exp Morphol 1982;69:141–9.PubMedGoogle Scholar
  9. 9.
    Fiorentino DF, Zlotnik A, Mosmann TR, Howard M, O’Garra A. I1–10 inhibits cytokine production by activated macrophages. J Immunol 1991;147:3815–22.PubMedGoogle Scholar
  10. 10.
    SchandenéL, Gerard C, Crusiaux A, Abramowicz D, Velu T, Goldman M. Interleukin-10 inhibits OKT3-induced cytokine release:in vitro comparison with pentoxifylline. Transplant Proc 1993;25:55–6.PubMedGoogle Scholar
  11. 11.
    Spagnoli GC, Juretic A, Schult-Thater E, et al. On the relative roles of interleukin-2 and interleukin-10 in the generation of lymphokine-activated killer cell activity. Cell Immunol 1993;146:391–405.PubMedCrossRefGoogle Scholar
  12. 12.
    Wegmann TG, Guilbert LJ, Mosmann TR, Lin H. The role of placental IL-10 in maternal-fetal immune interactions. In:Gergely J, Benczúr M, Erdei N, et al., eds. Progress in immunology VIII. Budapest:Springer-Verlag, 1992:857–9.Google Scholar
  13. 13.
    Gazzinelli RT, Oswald IP, James Sl, Sher A. IL-10 inhibits parasite killing and nitrogen oxide production by IFN-y-activated macrophages. J Immunol 1992;148:1792–6.PubMedGoogle Scholar
  14. 14.
    Kuhn R, Rajewsky K, Muller W. IL-4 and IL-10 deficient mice [Abstract]. 8th Int Cong Immunology, Budapest, Hungary, August 23–28, 1992:203.Google Scholar
  15. 15.
    Crainie M, Guilbert L, Wegmann TG. Expression of novel cytokine transcripts in the murine placenta. Biol Reprod 1990;43:999–1005.PubMedCrossRefGoogle Scholar
  16. 16.
    Kanzaki H, Crainie M, Lin H, Yui J, Guilbert LJ, Wegmann TG. The in-situ expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) mRNA at the maternal-fetal interface. Growth Factors 1991;5:69–74.PubMedCrossRefGoogle Scholar
  17. 17.
    Clark DA, Lea RG, Chaouat G, Pearce M, Abrams J. CDS+ suppressor cells and GM-CSF in the CBA-DBA/2 murine recurrent spontaneous abortion model [Abstract]. EOS 1992;12:82.Google Scholar
  18. 18.
    Clark DA, Lea RG, Denburg J, et al. Transforming growth factor-beta related suppressor factor in mammalian pregnancy decidua:homologies between the mouse and human in successful pregnancy and in recurrent unexplained abortion. In: Chaouat G, Mowbray JF, eds. Materno-fetal relationship:molecular and cellular biology. Colloque INSERM 1991;212:171–9.Google Scholar
  19. 19.
    Clark DA, Falbo M, Rowley RB, Banwatt D, Stedronska-Clark J. Active suppression of host-versus-graft reaction in pregnant mice, IX. Soluble suppressor activity obtained from allopregnant mouse decidua that blocks the response to interleukin 2 is related to TGF-ß. J Immunol 1988;141:383340.Google Scholar
  20. 20.
    Clark DA, Flanders KC, Banwatt D, et al. Murine pregnancy decidua produces a unique immunosuppressive molecule related to transforming growth factor 0–2. J Immunol 1990;144:3008–14.PubMedGoogle Scholar
  21. 21.
    Clark DA, Lea RG, Podor T, Daya S, Banwatt D, Harley C. Cytokines determining the success or failure of pregnancy. Ann NY Acad Sci 1991;626:524–36.PubMedCrossRefGoogle Scholar
  22. 22.
    Clark DA, Chaput A, Walker C, Rosenthal KL. Active suppression of hostversus-graft reaction in pregnant mice, VI. Soluble suppressor activity obtained from decidua of allopregnant mice blocks the response to IL-2. J Immunol 1985;134:1659–64.PubMedGoogle Scholar
  23. 23.
    Roberts AB, Sporn MB. The transforming growth factor-betas. In:Sporn MB, Roberts AB, eds. Peptide growth factors and their receptors:handbook of experimental pharmacology;vol 95. 1990:415–72.Google Scholar
  24. 24.
    Chen R-H, Ebner R, Derynck R. Inactivation of the type II receptor reveals two receptor pathways for the diverse TGF-ßactivities. Science 1993;26:1335–8.CrossRefGoogle Scholar
  25. 25.
    Lea RG, Flanders KC, Harley CB, Manuel J, Banwatt D, Clark DA. Release of a TGF-(32-related suppressor factor from postimplantation murine decidual tissue can be correlated with the detection of a subpopulation of cells containing RNA for TGF-ß2. J Immunol 1992;148:778–87.PubMedGoogle Scholar
  26. 26.
    Slapsys RM, Richards CD, Clark DA. Active suppression of host-versus-graft reaction in pregnant mice, VIII. The uterine decidua-association suppressor cell is distinct from decidual NK cells. Cell Immunol 1985;99:140–9.CrossRefGoogle Scholar
  27. 27.
    Hoskin DW, Brooks-Kaiser JC, Kaiser M, Murgita RA. Reactivity of monoclonal antibody IE5.B5 with a novel phenotypic marker expressed on a murine natural suppressor cell subset. Hybridoma 1992;11:203–15.PubMedCrossRefGoogle Scholar
  28. 28.
    Slapsys RM, Younglai E, Clark DA. A novel suppressor cell is recruited to decidua by fetal trophoblast-type cells. Reg Immunol 1988;1:182–9.PubMedGoogle Scholar
  29. 29.
    Clark DA, Chaput A, Tutton D. Active suppression of host-versus-graft reaction in pregnant mice, VII. Spontaneous abortion of allogeneic DBA/2 x CBA/J fetuses in the uterus of CBA/J mice correlates with deficient non-T suppressor cell activity. J Immunol 1986;136:1668–75.PubMedGoogle Scholar
  30. 30.
    Clark DA, Slapsys RM, Croy BA, Rossant J. Suppressor cell activity in uterine decidua correlates with success or failure of murine pregnancies. J Immunol 1983;131:540–2.PubMedGoogle Scholar
  31. 31.
    Clark DA, Drake B, Head JR, Stedronska-Clark J, Banwatt D. Decidua associated suppressor activity and viability of individual implantation sites of allopregnant C3H mice. J Reprod Immunol 1990;17:253–64.PubMedCrossRefGoogle Scholar
  32. 32.
    Clark DA, Banwatt D, Croy BA. Murine trophoblast failure and spontaneous abortion. Am J Reprod Immunol 1993;29:199–205.PubMedGoogle Scholar
  33. 33.
    Slapsys RM, Clark DA. Active suppression of host-versus-graft reaction in pregnant mice, IV. Local suppressor cells in decidua and uterine blood. J Reprod Immunol 1982;4:355–64.PubMedCrossRefGoogle Scholar
  34. 34.
    Waites GT, Whyte A. Effect of pregnancy on collagen-induced arthritis in mice. Clin Exp Immunol 1987;67:467–76.PubMedGoogle Scholar
  35. 35.
    Young EJ, Gomez CI. Enhancement of herpes virus type 2 infection in pregnant mice (40461). Proc Soc Exp Biol Med 1979;160:416–20.PubMedGoogle Scholar
  36. 36.
    Wegmann TG, Lin H, Guilbert L, Mosmann TR. Bidirectional cytokine interactions in the maternal-fetal relationship:is successful pregnancy a TH2 phenomenon? Immunol Today 1993;14:353–6.PubMedCrossRefGoogle Scholar
  37. 37.
    Clark DA, Kiger N, Guenet J-L, Chaouat G. Local active suppression and successful vaccination against spontaneous abortion in CBA/J mice. J Reprod Immunol 1987;10:79–85.PubMedCrossRefGoogle Scholar
  38. 38.
    Daya S, Clark DA. Identification of two species of suppressive factors of differing molecular weight released by in vitro fertilized human oocytes. Fertil Steril 1988;49:360–3.PubMedGoogle Scholar
  39. 39.
    Daya S, Rosenthal KL, Clark DA. Immunosuppressor factor(s) produced by decidua-associated suppressor cells-a proposed mechanism for fetal allograft survival. Am J Obstet Gynecol 1987;156:344–50.PubMedGoogle Scholar
  40. 40.
    Clark DA, Lea RG, Underwood J, et al. A subset of recurrent first trimester-aborting women show subnormal TGF-132 suppressor activity at the implantation site associated with miscarriage [Abstract]. EOS 1992;12:83.Google Scholar
  41. 41.
    Bulmer JN, Longfellow M, Ritson A. Leukocytes and resident blood cells in endometrium. Ann NY Acad Sci 1992;622:57–68.CrossRefGoogle Scholar
  42. 42.
    Vince G, Starkey P, Hirte H, Flanders K, Clark DA. TGF-ßproduction by large granular lymphocytes from human decidua. BSI-MFIG meet, April 1993, Liverpool.Google Scholar
  43. 43.
    Daya S, Johnson PM, Clark DA. Trophoblast induction of suppressor type cell activity in human endometrial tissue. Am J Reprod Immunol 1989;19:65–72.PubMedGoogle Scholar
  44. 44.
    Graham CH, Lala PK. Mechanism of control of trophoblast invasion in situ. J Cell Physiol 1991;148:228–34.PubMedCrossRefGoogle Scholar
  45. 45.
    Christmas SE, Bulmer J, Meager A, Johnson PM. Phenotypic and functional analysis of human CD3- decidual leukocyte clones. Immunology 1990;71:182–9.PubMedGoogle Scholar
  46. 46.
    Clark DA, Christmas S, Johnson PM, Banwatt D. Failure to detect TGF-ß2 mRNA or TGF-ßsuppressive activity associated with human CD3 decidual leukocyte clones [Abstract]. EOS 1992;12:82.Google Scholar
  47. 47.
    Subiza JL, Vinuela-Rodriguez R, Figueredo JGMA, De La Concha E. Development of splenic natural suppressor (NS) cells in Ehrlich tumor-bearing mice. Int J Cancer 1989;44:307–14.PubMedCrossRefGoogle Scholar
  48. 48.
    Kerbel RS, Theodorescu D. Tumor cell subpopulation interactions mediated by transforming growth factor ßmay contribute to clonal dominance of metastatically competent cells in primary tumours. In:Burger MM, Sordat B, Zinkernagel RM, eds. Cell to cell interaction. Basel:Karger, 1990:100–13.Google Scholar
  49. 49.
    Marquardt H, Lioubin MN, Ikeda T. Complete amino acid sequence of human transforming growth factor type ß2. J Biol Chem 1987;262:12127–31.PubMedGoogle Scholar
  50. 50.
    Constam DB, Phillipp J, Malipiero UV, ten Dijke P, Schachner M, Fontana A. Differential expression of transforming growth factor-ßl, -132 and -133 by glioblastoma cells, astrocytes, and microglia. J Immunol 1992;148:1404–10.PubMedGoogle Scholar
  51. 51.
    Bodmer S, Huber D, Heid I, Fontana A. Human glioblastoma cell derived transforming growth factor-132:evidence for secretion of both high and low molecular weight biologically active forms. J Neuroimmunol 1991;34:33–42.PubMedCrossRefGoogle Scholar
  52. 52.
    Hirte H, Clark DA. Generation of lymphokine-activated killer cells (LAK) in human ovarian carcinoma ascitic fluid:identification of transforming growth factor-beta (TGF-ß) as a suppressive factor. Cancer Immunol Immunother 1990;32:296–302.CrossRefGoogle Scholar
  53. 53.
    Hirte HW, Kaiser J, Rusthoven JJ, Mazurka J, O’Connell G. High molecular weight forms of transforming growth factor-a and transforming growth factor-[3 are present in ascites from human ovarian carcinoma [Abstract 1428 ]. Proc Am Assoc Cancer Res 1993;34:240.Google Scholar
  54. 54.
    McCune BK, Mullin BR, Flanders KC, Jaffurs WJ, Mullen LT, Sporn MB. Localization of transforming growth factor-ßisotypes in lesions of the human breast. Hum Pathol 1992;1 (suppl 23):13–20.CrossRefGoogle Scholar
  55. 55.
    King RJB, Wang DY, Daly RJ, Darbre PD. Approaches to studying the role of growth factors in the progression of breast tumours from the steroid sensitive to insensitive state. J Steroid Biochem 1989;34:133–8.PubMedCrossRefGoogle Scholar
  56. 56.
    Dublin EA, Barnes DM, Wang DY, King RJB, Levison DA. TGF alpha and TGF beta expression in mammary carcinoma. J Pathol 1993;170:15–22.PubMedCrossRefGoogle Scholar
  57. 57.
    Xie J, Gallagher G. Transforming growth factor-ßis not the major soluble immunosuppressor in the microenvironments of human breast tumours. Anticancer Res 1992;12:2117–22.PubMedGoogle Scholar

Copyright information

© Springer-Verlag New York, Inc. 1994

Authors and Affiliations

  • David A. Clark
  • Kathleen C. Flanders
  • Gill Vince
  • Phyllis Starkey
  • Hal Hirte
  • Justin Manuel
  • Jennifer Underwood
  • James Mowbray

There are no affiliations available

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