TRANSFORMING GROWTH-FACTOR-BETA INHIBITS PROGESTERONE-INDUCED ENKEPHALINASE EXPRESSION IN HUMAN ENDOMETRIAL STROMAL CELLS

The specific activity of enkephalinase in endometrial tissue of nonpre gnant ovulatory women is correlated in a highly significant, positive manner with the plasma level of progesterone. The specific activity an d levels of enkephalinase messenger ribonucleic acid and immunoreactiv e protein also are increased in human endometrial stromal cells in cul ture by treatment with a synthetic progestin, medroxyprogesterone acet ate (MPA), in a time- and dose-dependent manner. From an analysis of t he temporal relationship between the specific activity and hall-life o f enkephalinase in endometrial tissue and the level of progesterone in plasma, it appeared highly likely that some mechanism, in addition to progesterone withdrawal, was operative to reduce enkephalinase activi ty in endometrium during the late luteal phase of the ovarian cycle be fore progesterone levels had declined below those known to be effectiv e for progesterone action. In stromal cells previously (and concurrent ly) treated with MPA (10(-9) mol/L), the addition of transforming grow th factor-beta 1 (TGF beta 1) or TGF beta 2 (1 ng/mL) to the medium ca used a decrease in enkephalinase specific activity despite the continu ed presence of MPA. The half-life of enkephalinase (activity) in strom al cells treated with MPA plus TGF beta 1 was 2.8 days, which is simil ar to the computed half-life for enkephalinase in endometrial tissue d uring the mid- to late secretory phase of the endometrial cycle (2.5 d ays). Simultaneous treatment of endometrial stromal cells with MPA (10 (-9) mol/L) and TGF beta 1 (1 ng/mL) prevented the progestin-induced i ncrease in enkephalinase specific activity and immunoreactive enkephal inase protein. Thus, TGF beta acts to oppose the progesterone-induced increase in enkephalinase expression in endometrial stromal cells, eve n in the continued presence of MPA.