Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) is a well-known inducer of apoptotic cell death in many tumor cells. 1RAIL is expressed in human placenta, and cytotrophoblast cells express 1RAIL receptors. However, the role of TRAIL in human placentas and cytotrophoblast cells is not. well understood. In this study a trophoblast cell line, JEG-3, was used as a model system to examine the effect of TRAIL. on key intracellular signaling pathways involved in the control of trophoblastic cell apoptosis and survival JEG-3 cells expressed receptors for 1RAIL, death receptor (DR) 4, DR5, decoy receptor (OcR) 1 and DeR2. Recombinant human TRAIL (rhTRAIL) did not have a cytotoxic effect determined by MIT assay and did not induce apoptotic cell death determined by poly-(ADP-ribose) polymerase cleavage assay. rhTRAIL induced a rapid and transient nuclear translocation of nuclear factor-kB(NF-kB) determined by immunoblotting using nuclear protein extracts. rhTRAIL rapidly activated extracellular signal-regulated protein kinase (ERK) 1/2 as determined by immnoblotting for phospho-ERK1/2. However, c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (p38MAPK) and Akt (protein kinase B) were not activated by rhTRAIL. The ability of 1RAIL to induce NF-kB and ERK1/2 suggests that interaction between TRAIL and its receptors may play an important role in trophoblast cell function during pregnancy.

Trophoblasts, in the placenta, play a role for placental development as well as implantation in the early pregnancy. The characteristics and functions of trophoblast are identified by their localization and potency for proliferation, differentiation, and invasion. Thus, inadequate trophoblast cell death induces trophoblast dysfunction resulting in abnormal placental development and several gynecological diseases. Recently, it was reported that increased immortalization-upregulated protein-2 (IMUP-2) by hypoxia influences trophoblast apoptosis. However, IMUP-2 function on autophagy, which is type II programmed cell death remains unclear. In this study, we analyzed IMUP-2 expression in trophoblast cells (HTR8-SVneo) and compared IMUP-2 effects on cell death including apoptosis and autophagy in trophoblast regardless of IMUP-2 expression. Increased IMUP-2 in trophoblast by IMUP-2 gene transfection induces cell death, especially, apoptosis increases more than autophagy (p<0.05). However, the decreased IMUP-2 in trophoblasts after siRNA treatment decreased apoptosis with the decreased activities of caspase 3 and 7. The expressions of LC3 and MDC as an autophagosome makers and phosphorylated mTOR, which is a negative regulator for autophagy, increased. In addition, the S phase of cell cycle increased in trophoblasts when IMUP-2 expression decreased. Taken together, the alteration of IMUP-2 can control the balance between apoptosis and autophagy of trophoblasts resulting in functional involvement in placental development and in gynecological diseases by regulating the function of trophoblasts.

Implantation of the blastocyst into the maternal endometrium, mediated by well-differentiated primary cells of the placenta known as trophoblasts, grow in an invasive via complicated interaction with immune cells in the maternal myometrium. Placenta-derived stem cells (PDSCs), which is a fetal origin, display multi-lineages differentiation potential, and they are free of ethical concerns, easily accessible, abundant, and strongly immunosuppressive. However, the efficiency of PDSCs according to trophoblast invasion or immune modulation in implantation has not yet been evaluated. Here, we investigated the effects of PDSCs for trophoblast invasion as well as their potential for immune modulation of activated T cells when they co-cultured with PDSCs. Activated T cells and HTR-8SV/neo trophoblast cells were co-cultured with PDSCs according to cell dose-dependent manner. Activities for proliferation of T cells were analyzed by BrdU incorporation assay and cell invasions were estimated. Activation of T cells was significantly decreased in the group co-cultured with PDSCs comparing to normal fibroblast cells (p<0.05). In addition, trophoblast invasion by PDSCs have recorded a twofold increase than the normal fibroblast cells. These results contribute to our understanding of the potential roles of PDSCs, including immune modulation effects for trophoblast invasion in pregnancy, and provide a foundation for the development of new cell therapy-based strategies for the treatment of women with implantation.