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 Trophoblastsin Vitro

Abstract

The present study was conducted to determine whether T(3) receptor exists in early placental extravillous trophoblasts (EVTs) and evaluate the influence of T(3) 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 T(3) (10(-7) to 10(-9) m). The presence of T(3) 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 Abeta1 transcript and the T(3) receptor protein and exhibited significant levels of apoptosis in culture. Treatment with T(3) 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 T(3). These results demonstrate that T(3) receptor is present in early placental EVTs and that T(3) suppresses apoptosis by down-regulating the expression of Fas and Fas ligand. These findings are consistent with the hypothesis that T(3) promotes EVT invasion to the decidua by suppressing apoptosis in early pregnancy.

Anti-apoptotic effects of 3,5,3′-tri-iodothyronine in mouse hepatocytes

“…Although THs are known to exert many of their effects via classical regulation of gene transcription, a large number of their actions occur rapidly and are unaffected by inhibitors of transcription and protein synthesis (Yen 2001, Davis & Davis 2002, Incerpi 2005. Analyzing available data indicated that thyroid status influences sensitivity to apoptosis (Lin et al 1999, Qi et al 1999, Antonelli et al 2004, Laoag-Fernandez et al 2004, Verga Falzacappa et al 2006, we questioned whether T 3 -activated signaling could suppress DRLs-induced apoptosis. In this study, we found that THs counteract apoptotic effects of Fas/TNF and prevent hepatocyte apoptosis in a rapid non-genomic manner independent of transcriptional activity (Figs 1 and 2).…”

“…It is important that most of plasma membrane and cytosol targets of THs have been strongly circumstantially linked to mitogenic and antiapoptotic signaling pathways (Qi et al 1999, Laoag-Fernandez et al 2004, Verga Falzacappa et al 2006. For instance, THs were able to activate the Na C /H C exchanger (NHE) and reduce intracellular acidity produced by activated sodium currents in different cells (Wang et al 2003, D'Arezzo et al 2004.…”

Expression of thyroid hormone transporters in the human placenta and changes associated with intrauterine growth restriction

“…Both T3 and T4 stimulate EGF production by primary cytotrophoblasts, in turn 320 enhancing their survival [11]. In primary EVTs, T3 has been shown to suppress apoptosis [43] and promote invasion [12], whilst in an EVT-like cell line, T3 in conjunction with EGF, suppresses proliferation and increases cell motility [10]. The expression of MCT8, MCT10 and OATP1A2 in both cytotrophoblasts and EVTs during the 1 st trimester of pregnancy could allow TH cellular uptake into target cells and thus mediate TH action during early 325 placental development.…”

Triiodothyronine Modulates Thymocyte Migration

“…Whether or not T 3 also enhances thymocyte survival has not been determined. Yet, this hypothesis deserves investigation in view of the data showing that T 3 promotes a decrease in the expression of Fas and Fas ligand in cultured human trophoblastic cells, simultaneously with a suppression of apoptosis and reduced caspase-3 expression [52].…”