Abstract
During early pregnancy, the steroid hormone progesterone induces differentiation of uterine stroma to decidual cells, which regulate embryo-uterine interactions. The progesterone-induced signaling molecules that participate in the formation and function of decidua remain poorly understood. We recently utilized high-density oligonucleotide microarrays to identify several genes whose expression is markedly altered in pregnant uterus in response to RU486, a well characterized antagonist of the progesterone receptor (PR). Our study revealed that the gene encoding cytotoxic T-lymphocyte antigen-2beta (CTLA-2beta), a cysteine protease inhibitor, is expressed during PR-induced decidualization. The spatio-temporal expression of CTLA-2beta mRNA precisely overlapped with the decidual phase of pregnancy. Interestingly, administration of progesterone to estrogen-primed ovariectomized mice failed to induce CTLA-2beta expression. A concomitant artificial decidual stimulation was necessary to trigger this expression. Uteri of PR knockout mice failed to express this mRNA, even after a combined administration of steroid hormones and artificial stimulation. The uterine expression of CTLA-2beta was, therefore, dependent on PR as well as other unknown factor(s) associated with decidual response. To identify the molecular target(s) of CTLA-2beta,we analyzed its interaction with proteins present in soluble extracts prepared from day 7 pregnant uteri containing implanted embryos. A protein affinity strategy employing recombinant CTLA-2beta helped us to determine that cathepsin L, a cysteine protease, is one of its targets in the pregnant uterus. Consistent with this finding, expression of cathepsin L was detected in the giant trophoblast cells of the ectoplacental cone on day 7 of pregnancy. Collectively, our results support the hypothesis that expression of CTLA-2beta in the decidua may regulate implantation of the embryo by neutralizing the activities of one or more proteases generated by the proliferating trophoblast.
Highlights
During early pregnancy, the steroid hormone progesterone induces differentiation of uterine stroma to decidual cells, which regulate embryo-uterine interactions
Antiprogestin RU486 Down-regulates CTLA-2 Expression in the Pregnant Uterus—The pivotal role of progesterone during early pregnancy is likely to be mediated by a network of PRinduced genes [22]
The level of CTLA-2 mRNA on day 4 was about 15-fold higher than that on day 3 of gestation (Fig. 2B). These results indicated that CTLA-2 expression in the pregnant uterus is restricted between days 4 and 10 of gestation, an interval that precisely overlaps with the decidual phase
Summary
The steroid hormone progesterone induces differentiation of uterine stroma to decidual cells, which regulate embryo-uterine interactions. A protein affinity strategy employing recombinant CTLA-2 helped us to determine that cathepsin L, a cysteine protease, is one of its targets in the pregnant uterus Consistent with this finding, expression of cathepsin L was detected in the giant trophoblast cells of the ectoplacental cone on day 7 of pregnancy. To understand how progesterone regulates implantation, it is essential to identify a broader spectrum of genes that are regulated by PR1 during this process To achieve this goal, we employed RU486, a well characterized antagonist of PR function during pregnancy [16, 17]. We report the identification of a gene encoding cytotoxic T-lymphocyte antigen-2 (CTLA-2) that is induced downstream of PR in the pregnant uterus
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