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3,5,3'-Triiodothyronine Down-Regulates Fas and Fas Ligand Expression and Suppresses Caspase-3 and Poly (Adenosine 5'-Diphosphate-Ribose) Polymerase Cleavage and Apoptosis in Early Placental Extravillous Trophoblasts in Vitro

Department of Obstetrics and Gynecology (J.B.L.-F., H.Ma., H.Mu., A.L.H., T.M.), Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; and Reproductive Biology Unit (B.K.T.), Departments of Obstetrics and Gynecology and Cellular and Molecular Medicine, University of Ottawa, and Hormones, Growth, and Development Program, Ottawa Health Research Institute, Ottawa, Canada K1Y 4E9

Address all correspondence and requests for reprints to: Takeshi Maruo, M.D., Ph.D., Department of Obstetrics and Gynecology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan., E-mail: maruo{at}kobe-u.ac.jp.

The present study was conducted to determine whether T₃ receptor exists in early placental extravillous trophoblasts (EVTs) and evaluate the influence of T₃ on Fas/Fas ligand expression, caspase-3, and poly (ADP-ribose) polymerase (PARP) cleavage and apoptosis in cultured early placental EVTs. EVTs with invasive phenotype, isolated from normal placental explants from early pregnancy through preincubation on human fibronectin-coated dishes and exhibited cytokeratin 7 and human placental lactogen immunopositive staining, were cultured in the absence or presence of T₃ (10^–7 to 10^–9 M). The presence of T₃ receptor in cultured EVTs was examined by immunocytochemistry, RT-PCR, and Southern blot analysis. Fas sensitivity was determined by treating the cells with an agonistic Fas antibody. Apoptosis was assessed by terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling, flow cytometry, and Hoechst nuclear staining. Fas and Fas ligand expression and caspase-3 and PARP cleavage were evaluated by immunocytochemistry. Early placental EVTs expressed a 212-bp c-erb Aß1 transcript and the T₃ receptor protein and exhibited significant levels of apoptosis in culture. Treatment with T₃ reduced the expression of Fas and Fas ligand as well as cleavage of caspase-3 and PARP and suppressed apoptosis in cultured EVTs. Although addition of agonistic Fas antibody increased apoptosis in these cells, this response was markedly attenuated by the presence of T₃. These results demonstrate that T₃ receptor is present in early placental EVTs and that T₃ suppresses apoptosis by down-regulating the expression of Fas and Fas ligand. These findings are consistent with the hypothesis that T₃ promotes EVT invasion to the decidua by suppressing apoptosis in early pregnancy.

This work was supported in part by Grants in Aid for Scientific Research 13877274 from the Japanese Ministry of Education, Science, and Culture, the Ogyaa-Donation Foundation of Japan Association of Obstetricians and Gynecologists, and Postdoctoral Fellowship (to J.B.L.-F.) and Visiting Professorship (to B.K.T.) of the Japan Society for the Promotion of Science.

Abbreviations: EVT, Extravillous trophoblast; FBS, fetal bovine serum; FN, fibronectin; hPL, human placental lactogen; PARP, poly (ADP-ribose) polymerase; SSC, saline sodium citrate; TUNEL, terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling.

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