Interleukin 1β and Progesterone Stimulate Activin A Expression and Secretion From Cultured Human Endometrial Stromal Cells

Abstract

Steroid hormones, cytokines, and growth factors have a major role in evoking local endometrial changes needed for trophoblast implantation. In the present study, the effect of interleukin-1β (IL-1β), 17-β estradiol (E2), and progesterone (Pr) on activin A and follistatin (FS) secretion from cultured human endometrial stromal cells (HESCs) is evaluated. HESCs were obtained from healthy human endometrial samples (n = 8) collected from healthy women. The cells were cultured and stimulated with E2 (10^-7 M, 10 ^-6 M), Pr (10 ^-7 M, 10 ^-6 M), IL-1β (500 pg/mL), IL-1β (500 pg/mL) + E2 (10 ^-6 M), and IL-1β (500 pg/mL) + Pr (10 ^-6 M). Activin A and FS secretion and mRNA expression were assayed by enzyme-linked immunosorbent assay and semiquantitative reverse transcriptase-polymerase chain reaction, respectively. Pr (10 ^-7 M, 10 ^-6 M) significantly increased activin A secretion and mRNA expression from HESCs, but E2 did not show remarkable effects. The addition of IL-1β (P< .001), IL- 1β + E2 (P < .01), and IL-1β + Pr (P< .001). significantly stimulated activin A secretion and mRNA expression, compared to untreated cells. Activin A expression and secretion after the coincubation of IL-1β+ Pr were significantly higher than after IL-1βand IL-1β+ E2 stimuli ( P< .01 and P< .001, respectively). Neither Pr nor E2 and IL-1β had a significant effect on FS secretion and expression. IL-1βand Pr stimulated activin A but not FS secretion from cultured HESCs, and the effect of IL-1βwas augmented by Pr. These findings, together with the evidence that activin A is involved in trophoblast implantation, suggest the existence of a complex cross-talk by which the ovary, through Pr secretion, and the embryo, through IL-1β production, may trigger the endometrial induction of activin A and consequently timing implantation.

Keywords

Activin A follistatin cytokines embryo pregnancy implantation

Get full access to this article

View all access options for this article.

References

Vale W , Rivier C , Hsueh A , et al. Chemical and biological characterization of the inhibin family of protein hormones. Recent Prog Horm Res. 1988;44:1-34.

Petraglia F , Florio P , Luisi S , et al. Expression and secretion of inhibin and activin in normal and neoplastic uterine tissues: high levels of serum activin A in women with endometrial and cervical carcinoma. J Clin Endocrinol Metab. 1998;83:1194-1200.

Leung PH , Salamonsen LA , Findlay JK . Immunolocalization of inhibin and activin subunits in human endometrium across the menstrual cycle. Hum Reprod. 1998;13:3469-3477.

Otani T , Minami S , Kokawa K , Shikone T , Yamoto M , Nakano R . Immunohistochemical localization of activin A in human endometrial tissues during the menstrual cycle and in early pregnancy. Obstet Gynecol. 1998;91:685-692.

Jones RL , Salamonsen LA , Critchley HO , Rogers PA , Affandi B , Findlay JK . Inhibin and activin subunits are differentially expressed in endometrial cells and leukocytes during the menstrual cycle,in early pregnancy and in women using progestin-only contraception. Mol Hum Reprod. 2000;6:1107-1117.

Jones RL , Salamonsen LA , Zhao YC , Ethier JF , Drummond AE , Findlay JK . Expression of activin receptors, follistatin and betaglycan by human endometrial stromal cells;consistent with a role for activins during decidualization. Mol Hum Reprod. 2002;8:363-374.

Florio P , Severi FM , Luisi S , et al. Endometrial expression and secretion of activin A, but not follistatin, increase in the secretory phase of the menstrual cycle. J Soc Gynecol Investig. 2003;10:237-243.

Mylonas I , Jeschke U , Wiest I , et al. Inhibin/activin subunits alpha, beta-A and beta-B are differentially expressed in normal human endometrium throughout the menstrual cycle. Histochem Cell Biol. 2004;122:461-471.

Caniggia I , Lye SJ , Cross JC . Activin is a local regulator of human cytotrophoblast cell differentiation. Endocrinology. 1997;138:3976-3986.

10.

Jones RL , Salamonsen LA , Findlay JK . Activin A promotes human endometrial stromal cell decidualization in vitro. J Clin Endocrinol Metab. 2002;87:4001-4004.

11.

Tierney EP , Giudice LC . Role of activin A as a mediator of in vitro endometrial stromal cell decidualization via the cyclic adenosine monophosphate pathway. Fertil Steril. 2004;81:899-903.

12.

Jones RL , Salamonsen LA , Findlay JK . Potential roles for endometrial inhibins, activins and follistatin during human embryo implantation and early pregnancy. Trends Endocrinol Metab. 2002;13:144-150.

13.

Florio P , Rossi M , Sigurdardottir M , et al. Paracrine regulation of endometrial function: interaction between progesterone and corticotropin-releasing factor (CRF) and activin A. Steroids. 2003;68:801-807.

14.

Luisi S , Florio P , Reis FM , Petraglia F . Expression and secretion of activin A: possible physiological and clinical implications. Eur J Endocrinol. 2001;145:225-236.

15.

Edwards RG . Physiological and molecular aspects of human implantation. Hum Reprod. 1995;10:1-13.

16.

Tabibzadeh S , Sun XZ . Cytokine expression in human endometrium throughout the menstrual cycle. Hum Reprod. 1992;7:1214-1221.

17.

Simon C , Gimeno MJ , Mercader A , et al. Embryonic regulation of integrins beta 3, alpha 4, and alpha 1 in human endometrial epithelial cells in vitro. J Clin Endocrinol Metab. 1997;82:2607-2616.

18.

Simon C , Frances A , Piquette G , Hendrickson M , Milki A , Polan ML . Interleukin-1 system in the materno-trophoblast unit in human implantation: immunohistochemical evidence for autocrine/paracrine function. J Clin Endocrinol Metab. 1994;78:847-854.

19.

Noyes RW , Hertig AT , Rock J.Dating the endometrial biopsy. Am J Obstet Gynecol. 1975;122:262-263.

20.

Di Blasio AM , Giraldi FP , Vigano P , Petraglia F , Vignali M , Cavagnini F . Expression of corticotropin-releasing hormone and its R1 receptor in human endometrial stromal cells. J Clin Endocrinol Metab. 1997;82:1594-1597.

21.

Chomczynski P , Sacchi N . Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987;162:156-159.

22.

Vigano P , Somigliana E , Mangioni S , Vignali M , Vignali M , Di Blasio AM . Expression of interleukin-10 and its receptor is upregulated in early pregnant versus cycling human endometrium. J Clin Endocrinol Metab. 2002;87:5730-5736.

23.

Altschul SF , Madden TL , Schaffer AA , et al. Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res. 1997;25:3389-3402.

24.

Popovici RM , Kao LC , Giudice LC . Discovery of new inducible genes in in vitro decidualized human endometrial stromal cells using microarray technology. Endocrinology. 2000;141:3510-3513.

25.

Wu WX , Brooks J , Glasier AF , McNeilly AS . The relationship between decidualization and prolactin mRNA and production at different stages of human pregnancy. J Mol Endocrinol. 1995;14:255-261.

26.

Feijen A , Goumans MJ , van den Eijnden-van Raaij AJ . Expression of activin subunits, activin receptors and follistatin in postimplantation mouse embryos suggests specific developmental functions for different activins. Development. 1994;120:3621-3637.

27.

Vigano P , Lattuada D , Mangioni S , et al. Cycling and early pregnant endometrium as a site of regulated expression of the vitamin D system. J Mol Endocrinol. 2006;36:415-424.

28.

Zhao D , Lebovic DI , Taylor RN . Long-term progestin treatment inhibits RANTES (regulated on activation, normal T cell expressed and secreted) gene expression in human endometrial stromal cells. J Clin Endocrinol Metab. 2002;87:2514-2519.