Induction of cytotoxic T-lymphocyte antigen-2beta, a cysteine protease inhibitor in decidua: a potential regulator of embryo implantation.
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.
Cheon
Yong-Pil
YP
Department of Veterinary Biosciences, University of Illinois, Urbana-Champaign, Urbana, Illinois 61802, USA.
DeMayo
Francesco J
FJ
Bagchi
Milan K
MK
Bagchi
Indrani C
IC
D000818:Animals; D000943:Antigens, Differentiation / Q000096:biosynthesis* / Q000737:chemistry; D016367:Baculoviridae / Q000235:genetics; D015152:Blotting, Northern; D056668:Cathepsin L; D002403:Cathepsins / Q000378:metabolism / Q000494:pharmacology; D002455:Cell Division; D002460:Cell Line; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D018076:DNA, Complementary / Q000378:metabolism; D003656:Decidua / Q000473:pathology*; D015536:Down-Regulation; D010064:Embryo Implantation; D005260:Female; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007313:Insecta; D051379:Mice; D018345:Mice, Knockout; D015735:Mifepristone / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D011247:Pregnancy; D011270:Pregnancy, Animal; D012333:RNA, Messenger / Q000378:metabolism; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors; D011994:Recombinant Proteins / Q000737:chemistry; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D013997:Time Factors; D014599:Uterus / Q000378:metabolism / Q000473:pathology
D000943:Antigens, Differentiation; D015853:Cysteine Proteinase Inhibitors; D018076:DNA, Complementary; D012333:RNA, Messenger; D011980:Receptors, Progesterone; D011994:Recombinant Proteins; D015735:Mifepristone; D002403:Cathepsins; D003546:Cysteine Endopeptidases; D056668:Cathepsin L; C534278:Ctsl protein, mouse