Induction of Thioredoxin, a Redox-Active Protein, by Ovarian Steroid Hormones during Growth and Differentiation of Endometrial Stromal Cells in Vitro

Abstract

Human thioredoxin (hTrx) is a cellular redox-active protein that catalyzes dithiol/disulfide exchange reactions, thus controlling multiple biological functions, including cell growth-promoting activity. Here we show that the expression of hTrx protein and messenger RNA was up-regulated by incubation with 17β-estradiol (E₂) in primary culture of stromal cells isolated from human endometrium. Maximal enhancement of hTrx protein and messenger RNA was observed after 6–12 h of incubation with 10–100 nm E₂, and the enhancing effect was suppressed by tamoxifen, an estrogen antagonist. Release of hTrx into the culture medium was markedly augmented after 5-day exposure of E₂ plus progesterone (P) accompanied by in vitro differentiation of endometrial stromal cells (decidualization). Immunocytochemical studies showed that hTrx was localized in the nucleus, nucleolus, and cytosol in the stromal cells. Strongly enhanced immunoreactivity for hTrx was observed in the E₂-treated cells, whereas there was no apparent difference in the pattern of subcellular localization among the untreated and E₂- and/or P-treated cells. Although 1–50 μg/ml recombinant hTrx alone did not promote endometrial stromal cell growth, epidermal growth factor-dependent mitogenesis was additively enhanced by hTrx. Our results indicate that hTrx modulates endometrial cell growth, acting as a comitogenic factor for epidermal growth factor, which is known to be a mediator of estrogen action. It is also suggested that hTrx is deeply involved in the hormonal control of the endometrium by E₂ and P, playing a regulatory role in endometrial cell growth and differentiation.