Abstract
Progesterone is a pleiotropic regulator of uterine function required for the maintenance of pregnancy in mammals. A major action of progesterone is to induce expression of genes encoding for secretory proteins of the uterine endometrium. These proteins participate in several roles deemed essential for survival of the conceptus and include enzymes, transport proteins, and regulatory proteins. Several serpins have been identified as being part of the milieu of secretory proteins in the progesterone-dominated uterus. Among these are plasminogen activator inhibitor-1, induced by progesterone in cultured human endometrial cells (Miyauchi et al., 1995; Lockwood et al., 1995), and α1-antitrypsin, which is synthesized by human endometrium during pregnancy (Fay et al., 1990) and also can enter uterine fluid as a serum transudate (Bany and McRae, 1992). These proteins likely inhibit serine proteinases secreted by the uterus and placenta and may limit remodeling of the endometrium, participate in local hemostasis and regulate placental invasiveness. In addition to these well-known serpins, the uterus of certain species of ungulates each produce one or more members of a subfamily of serpins that are characterized by endometrial site of synthesis, sequence homology to each other, and weak or no known antiproteinase activity. This chapter will concentrate on the most well-characterized of these uterine-specific serpins — a glycoprotein of the sheep uterus called uterine milk protein (UTMP) — and will compare the properties of this protein to other uterine serpins. Uterine milk protein is the most abundant steroid-induced protein yet described and gram quantities can be obtained from the uterus of a single unilaterally-pregnant ewe (Moffatt et al., 1987a). There is evidence to implicate UTMP in inhibition of lymphocyte funciton and in binding interactions with placental secretory proteins. It is also possible that UTMP acts as a carrier protein to transport maternal products across the placenta.
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References
Bairoch, A. and Boeckmann, B. (1991) The SWISS-PROT protein sequence data bank. Nucl. Acids Res. 19: 2247–2249.
Bany, B.M. and McRae, A.C. (1992) Uterine uptake of α2-macroglobulin and α1-proteinase inhibitor from the blood during early implantation in the mouse. Biol. Reprod. 47: 514–519.
Bata, J. and Revillard, J.P. (1981) Interaction between α1antitrypsin and lymphocyte surface proteases: immunoregulatory effects. Agents Actions 11: 614–617.
Baumbach, G.A., Ketcham, C.M., Richardson, D.E., Bazer, F.W. and Roberts, R.M. (1986) Isolation and characterization of a high molecular weight form of uteroferrin from uterine secretions and allantoic fluid of pigs. J. Biol. Chem. 261: 12869–12878.
Bazer, F.W., Roberts, R.M., Basha, S.M.M., Zavy, M.T., Caton, D. and Barron, D.H. (1979) Method for obtaining uterine secretions from unilaterally pregnant ewes. J Anim Sci 49: 1522–1527.
Breit, S.N., Luckhurst, E. and Penny, R. (1983) The effect of α1 antitrypsin on the proliferative response of human peripheral blood lymphocytes. J. Immunol. 130: 681–686.
Buhi, W.C., Ducsay, C.A., Bazer, F.W. and Roberts, R.M. (1982) Iron transfer between the purple phosphatase uteroferrin and transferrin and its possible role in iron metabolism of the fetal pig. J. Biol. Chem. 257: 1712–1723.
Carrell, R.W., Evans, D.L. and Stein, P.E. (1991) Mobile reactive centre of serpins and the control of thrombosis. Nature 353: 576–578.
Carrell, R.W., Pemberton, P.A. and Boswell, D.R. (1987) The serpins: evolution and adaptation in a family of protease inhibitors. Cold Spring Harbor Symp. Quant. Biol. 52: 527–535.
Fay, T.N., Lindenberg, S., Teisner, B., Westergaard, L.G., Westergaard, J.G. and Grudzinskas, J.G. (1990) Identification of specific serum proteins synthesized de novo by monolayer cultures of glandular cells of gestational endometrium. Hum. Reprod. 5: 14–18.
Faust, P.L., Chirgwin, J.M. and Kornfeld, S. (1987) Renin, a secretory glycoprotein, acquires phosphomannosyl residues. J. Cell Biol. 105: 1947–1955.
Gottshall, S.L. and Hansen, P.J. (1992) Regulation of leucocyte subpopulations in the sheep endometrium by progesterone. Immunology 76: 636–641.
Hansen, P.J. (1995) Interactions between the immune system and the ruminant conceptus. J. Reprod. Fertil. Suppl. 49: 69–82.
Hansen, P. J., Bazer, F. W. and Segerson, E. C. (1986) Skin graft survival in the uterine lumen of ewes treated with progesterone. Am. J. Reprod. Immunol. Microbiol. 12: 48–54.
Hansen, P.J. and Foti, S.A. (1986) Proteins similar to the major proteins in uterine secretions of pregnant ewes are also found in colostrum. J. Anim. Sci. 63 (Suppl. 1 ): 53–54 (abstr).
Hansen, P.J., Ing, N.H., Moffatt, R.J., Baumbach, G.A., Saunders, P.T.K., Bazer, F.W. and Roberts, R.M. (1987a) Biochemical characterization and biosynthesis of the uterine milk proteins of the pregnant sheep uterus. Biol Reprod 36: 405–418.
Hansen, P.J. and Liu, W.-J. (1994) Biochemical/physiological properties of endometrial serpin-like proteins. Adv. Contracept. Delivery Sys. 10: 339–353.
Hansen, P.J. and Newton, G.R. (1988) Binding of immunoglobul ins to the major progesterone-induced proteins of the sheep uterus. Arch. Biochem. Biophys. 260: 208–217.
Hansen, P.J., Segerson, E.C. and Bazer, F.W. (1987b) Characterization of immunosuppressive substances in the basic protein fraction of uterine secretions from pregnant ewes. Biol Reprod 36: 393–404.
Herzog V., Neumuller, W. and Holzmann, B. (1987) Thyroglobulin, the major and obligatory exportable protein of thyroid follicle cells, carries the lysosomal recognition marker mannose-6-phosphate. EMBO J. 6: 555–560.
Huang, X. and Miller, W. (1991) A time-efficient, linear-space local similarity algorith. Adv. Appl. Math. 12: 337–357.
Ing, N.H. and Roberts, R.M. (1989) The major progesterone-modulated proteins secreted into the sheep uterus are members of the serpin superfamily of serine protease inhibitors. J. Biol. Chem. 264: 3372–3379.
Ing N.H., Francis H., Mc Donnell J.J., Amann J.F. and Roberts, R.M. (1989) Progesterone induction of the uterine milk proteins: major secretory proteins of sheep endometrium. Biol. Reprod. 41: 643–654.
Komiyama, T., Ray, C.A., Pickup, D.J., Howard, A.D., Thornberry, N.A., Peterson, E.P. and Salvesen, G. (1994) Inhibition of interleukin-1 β converting enzyme by the cowpox virus serpin CrmA. An example of cross-class inhibition. J. Biol. Chem. 269: 19331–19337.
Lander Chacin, M.F., Hansen, P.J. and Drost, M. (1990) Effects of stage of the estrous cycle and steroid treatment on uterine immunoglobulin content and polymorphonuclear leukocytes in cattle. Theriogenology 34: 1169–1184.
Leslie, M.V., Hansen, P.J. and Newton, G.R. (1990) Uterine secretions of the cow contain proteins that are immunochemically related to the major progesterone-induced proteins of the sheep uterus. Domest. Anim. Endocrinol. 7: 517–526
Leslie M.V. and Hansen, P.J. (1991) Progesterone-regulated secretion of the serpin-like proteins of the ovine and bovine uterus. Steroids 56: 589–597
Low, B. G. and Hansen, P.J. (1988) Immunosuppressive actions of steroids and prostaglandins secreted by the placenta and uterus of the cow and sheep. Am. J. Reprod. Immunol. Microbiol. 18: 71–75.
Liu, W.-J. and Hansen, P.J. (1993) Effect of the progesterone-induced serpin-like proteins of the sheep endometrium on natural-killer cell activity in sheep and mice. Biol. Reprod. 49: 1008–1014.
Liu, W.-J. and Hansen, P.J. (1995a) Progesterone-induced secretion of dipeptidyl peptidase-IV (cell differentiation antigen-26) by the uterine endometrium of the ewe and cow that costimulates lymphocyte proliferation. Endocrinology 136: 779–787.
Liu, W.-J. and Hansen, P.J. (1995b) Pathways for inhibition of lymphocyte activation by uterine milk proteins. Am. J. Reprod. Immunol. 33: 445 (abstr.).
Liu, W.J. and Hansen, P.J. (1996) Binding of endometrial serpin-like proteins to peripheral blood lymphocytes in sheep. Am. J. Reprod. Immunol., 453 (abstr.).
Lockwood, C.J., Krikun, G., Papp, C., Aigner, S. and Schatz, F. (1995) Biological mechanisms underlying the clinical effects of RU 486: modulation of cultured endometrial stromal cell plasminogen activator and plasminogen activator inhibitor expression. J. Clin. Endocrinol. Metab. 80: 1100–1105.
Malathy, M.-V., Imakawa, K., Simmen, R.C.M. and Roberts, R.M. (1990) Molecular cloning of the uteroferrinassociated protein, a major progesterone-induced serpin secreted by the porcine uterus, and the expression of its mRNA during pregnancy. Mol. Endocrinol. 4: 428–440.
Mathialagan, N., Paul, L. and Roberts, R.M. (1995) Sheep uterine serpins are inhibitors of aspartic proteinases rather than serine proteinases. Biol. Reprod. 52 (Suppl. 1 ): 186 (abstr.).
Mathialagan, N., Hansen, T.R. and Roberts, R.M. (1997) Pepsin inhibitory activity of the uterine serpins. In: Chemistry and Biology of Serpins(F.C. Church, D.D. Cunningham, D. Ginsberg, and M. Hoffman, eds.) Plenum, New York. (abstr.)
Miyauchi, A., Osuga, Y. and Taketani, Y. (1995) Effects of steroid hormones on fibrinolytic system in cultured human endometrial cells. Endocrine J. 42: 57–62.
Moffatt R.J., Bazer, F.W., Hansen P.J., Chun, P.W. and Roberts, R.M. (1987b) Purification, secretion and immunocytochemical localization of the uterine milk proteins, major progesterone-induced proteins in uterine secretions of the sheep. Biol Reprod 36: 419–430.
Moffatt, R.J., Bazer, F.W., Roberts, R.M. and Thatcher, W.W. (1987a) Secretory function of the ovine uterus: effects of gestation and steroid replacement therapy. J. Anim. Sci. 65: 1400–1410
Murray, M.K., Malathy, P.V., Bazer, F.W. and Roberts, R.M. (1989) Structural relationship, biosynthesis, and immunocytochemical localization of uteroferrin-associated basic glycoprotein. J Biol Chem 264: 4143–4150
Newton, G. R., Hansen, P. J., Bazer, F. W., Leslie, M. V., Stephenson, D. C. and Low, B. G. (1989) Presence of the major progesterone-induced proteins of the sheep endometrium in fetal fluids. Biol. Reprod. 40: 417–424.
Pemberton, P.A., Stein, P.E., Pepys, M.B., Potter, J.M. and Carrell, R.W. (1988) Hormone binding globulins undergo serpin conformational change in inflammation. Nature (Lond) 336: 257–258.
Perlmutter, D.H., Glover, G.I., Rivetna, M., Schasteen, C.S. and Fallon, R.J. (1990) Identification of a serpinenzyme complex receptor on human hepatoma cells and human monocytes. Proc. Natl. Acad. Sci. USA. 87: 3753–3757.
Skopets, B. and Hansen, P.J. (1993) Identification of the predominant proteins in uterine fluids of unilaterally pregnant ewes that inhibit lymphocyte proliferation. Biol. Reprod. 49: 997–1007.
Skopets, B., Liu, W.-J. and Hansen, P.J. (1995) Effects of endometrial serpin-like proteins on immune responses in sheep. Am. J. Reprod. Immunol. 33: 86–93.
Sonnhammer, E.L.L. and Kahn, D. (1994) Modular arrangement of proteins as inferred from analysis of homology. Protein Sci. 3: 482–492.
Stephenson D.C. and Hansen, P.J. (1990) Induction by progesterone of immunosuppressive activity in uterine secretions of ovariectomized ewes. Endocrinology 126: 3168–3178
Stephenson D.C., Low, B.G., Newton, G.R., Leslie, M.V., Hansen, P.J. and Bazer, F. W. (1989) Secretion of the major progesterone-induced proteins of the sheep uterus by caruncular and intercaruncular endometrium of the pregnant ewe from days 20–140 of gestation. Domest. Anim. Endocrinol. 6: 349–362
Tchórzewski, H., Fornalczyk, E. and Pasnik, J. (1995) Protease inhibitors diminish lymphocyte stimulation in vitro. FEBS Lett. 46: 237–240.
Weiss, A. and Littleman, D. (1994) Signal transduction by lymphocyte antigen receptors. Cell 76: 631–634.
Zhang, X., Miller, B.G. and Stone, G.M. (1989) Protein secretion by the endometrium during pregnancy in the ewe. Reprod. Fertil. Dev. 1: 15–30.
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Hansen, P.J., Liu, WJ. (1997). Biology of Progesterone-Induced Uterine Serpins. In: Church, F.C., Cunningham, D.D., Ginsburg, D., Hoffman, M., Stone, S.R., Tollefsen, D.M. (eds) Chemistry and Biology of Serpins. Advances in Experimental Medicine and Biology, vol 425. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-5391-5_14
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DOI: https://doi.org/10.1007/978-1-4615-5391-5_14
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