Death Receptor Fas/Apo-1/CD95 Expressed by Human Placental Cytotrophoblasts Does Not Mediate Apoptosis1

Abstract

Trophoblasts, the fetal cells that line the villous placenta and separate maternal blood from fetal tissue, express both Fas antigen and the tumor necrosis factor (TNF) receptor p55 (TNFRp55), two members of the TNF receptor family that contain a cytoplasmic "death domain" that mediates apoptotic signals. We show that Fas mRNA expressed by cultured villous cytotrophoblasts isolated from term placentas encodes transmembrane sequences and that the protein is full-length (approximately 45 kDa), suggesting that the product is an active plasma membrane-anchored receptor. Its location on the cell surface was confirmed by cellular ELISA analysis of live cells. Although cytotrophoblast apoptosis was induced by TNFalpha, and both anti-Fas antibody (CH11) and FasL-expressing T lymphocyte hybridoma (activated A1.1) cells induced HeLa cell apoptosis, neither CH11 antibody nor activated A1.1 cells stimulated apoptosis in term or first-trimester cytotrophoblasts or in term syncytiotrophoblasts. We conclude that Fas- but not TNFRp55-mediated apoptosis is blocked in primary villous trophoblasts. These data suggest that the Fas response is specifically inactivated by unknown mechanisms to avoid autocrine or paracrine killing by Fas ligand constitutively expressed on neighboring cyto- or syncytiotrophoblasts.

Differential Expressions of Fas and Fas Ligand in Human Placenta

“…In placenta, syncytiotrophoblasts are in direct contact with maternal peripheral blood lymphocytes and FasL, expressed in activated or cytotoxic T-lymphocytes, natural killer cells and neutrophils, might bind to Fas on these target cells and induces apoptosis (13,14). Although it was reported Fas-but not TNF receptor p55-mediated apoptosis was blocked in primary villous trophoblasts (15), the bare staining for Fas in syncytiotrophoblasts seems to make sense in that the Fas response may be avoided by FasL constitutively expressed on neighboring cyto-or syncytiotrophoblasts and activated maternal lymphocytes. The notable localization of Fas in fetal vessels might have some clinical implications and trophoblast apoptosis is a significant feature of early-onset intrauterine growth restriction (16).…”

XAF1 Mediates Tumor Necrosis Factor-α-induced Apoptosis and X-linked Inhibitor of Apoptosis Cleavage by Acting through the Mitochondrial Pathway

“…The Fas/Fas ligand system represents one of the most common and well characterized TNF death receptor apoptotic pathways. Despite expressing both Fas and Fas ligand, trophoblast cells isolated from first trimester placentas are resistant to Fas-mediated apoptosis under normal conditions (1)(2)(3). However, in contrast to Fas ligand-induced apoptosis, first trimester trophoblast cells have been shown to be sensitive to TNF-␣-mediated apoptosis (1,2,4,5).…”

“…Despite expressing both Fas and Fas ligand, trophoblast cells isolated from first trimester placentas are resistant to Fas-mediated apoptosis under normal conditions (1)(2)(3). However, in contrast to Fas ligand-induced apoptosis, first trimester trophoblast cells have been shown to be sensitive to TNF-␣-mediated apoptosis (1,2,4,5). Since both Fas and TNF-R1, the death receptor that mediates TNF-␣-induced apoptosis (6,7), share several components of the intracellular apoptotic cascade, it is unknown how first trimester trophoblast cells remain resistant to Fas but sensitive to TNF-␣-induced apoptosis.…”

Pregnancy and the immune system: between tolerance and rejection

“…This without endangering the trophoblasts themselves. Indeed, CD95 present on trophoblasts does not seem to transduce apoptotic signals in these cells (Payne et al, 1999). Annexin II is secreted by the placenta and might inhibit lymphoproliferation and secretion of maternal immunoglobulins (Fig.…”