Macrophages and apoptotic cell clearance during pregnancy.

BACKGROUND: During implantation, apoptosis is critical for the appropriate tissue remodeling of the maternal decidua and invasion of the developing embryo, yet the regulation of apoptosis is also imperative for a successful pregnancy. The quick and effective removal of apoptotic cells by tissue macrophages represents an essential process, which prevents the release of self-antigens, and in the case of pregnancy, paternal alloantigens. METHODS OF STUDY: Recent studies have shown that the process of apoptotic cell clearance is not a neutral event, but rather an active one that induces macrophage production of anti-inflammatory cytokines and survival factors. Apoptotic cell clearance is, therefore, necessary for the resolution of inflammatory conditions, which during pregnancy could have lethal consequences. CONCLUSIONS: The function of the maternal immune system during implantation and throughout pregnancy is, therefore, an important area of investigation. This review will discuss the role of decidual macrophages in apoptotic cell clearance during pregnancy.

Epithelial ovarian cancer cells secrete functional Fas ligand.

The Fas/Fas ligand (FasL) system has been suggested to play an important role in the establishment of an immune privilege status of the tumor by inducing Fas-mediated apoptosis in tumor-specific lymphocytes. However, the role of cell surface-expressed FasL in tumor cell protection has recently become controversial. In this study, we have demonstrated that ascites-derived epithelial ovarian cancer cells lack membranal FasL but constitutively secrete whole, intracellular FasL (37 kDa) via the release of microvesicles. In contrast, normal ovarian surface epithelial cells express, but do not secrete, FasL. We have also identified a heavily glycosylated form of secreted FasL (48 kDa), associated with microvesicles isolated directly from the ascites fluid of patients with ovarian cancer. Following the disruption of the microvesicle membrane, both the 37-kDa and 48-kDa forms of secreted FasL were able to trigger Fas-mediated apoptosis in Jurkat T cells. These results suggest that the release of secreted FasL, and not the membrane form, may provide a mechanism by which tumors might counterattack Fas-bearing immune cells, thus facilitating their escape from immune surveillance and promoting tumor cell survival.

Role of the Fas/Fas ligand system in female reproductive organs: survival and apoptosis.

For centuries, the question of "whether there is life after death" has intrigued the mind of philosophers and the same question fascinates researchers in the field of apoptosis today. The death of a cell is by no means the end of the story. On the contrary, growing evidence suggests that the clearance of apoptotic bodies by macrophages is an important regulatory component in tissue renewal. Without death by apoptosis, the life of reproductive tissues and their function would not be possible. The survival signals that counteract cell death also prepare the cells for apoptosis, and dead cells are important stimuli for tissue survival. The Fas/Fas ligand system is an important mediator of apoptosis and is an excellent example of this apparently contradictory phenomenon.

Differential regulation and function of the Fas/Fas ligand system in human trophoblast cells.

Trophoblast rejection, which is characterized by increased apoptosis, is mediated by T helper (Th)-1, or proinflammatory, cytokines, whereas Th-2, or anti-inflammatory, cytokines confer immune protection and facilitate implantation. We investigated the role of both types of cytokines on the expression and function of the Fas/Fas ligand (FasL) apoptotic pathway in trophoblast cells. First-trimester human trophoblast primary-culture cells as well as A3 and HTR/8 trophoblast cell lines were treated with proinflammatory cytokines such as interferon-gamma (IFN-gamma) and tumor necrosis factor alpha (TNFalpha) and with the anti-inflammatory cytokines interleukin (IL)-6 and IL-10. Sensitivity to Fas-mediated apoptosis was measured using an activating anti-Fas monoclonal antibody. Cell viability was evaluated using the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) and CellTiter 96 assay. Fas/FasL mRNA and protein expression levels were determined using reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis, respectively. Trophoblast cells normally express FasL, but low levels of Fas, and they are resistant to Fas-mediated apoptosis. IFN-gamma and TNFalpha promote Fas expression and sensitivity, whereas IL-6 and IL-10 increase the resistance of trophoblast cells to Fas-mediated apoptosis. Furthermore, IL-10 treatment activates FLICE-like inhibitory protein (FLIP), a downstream inhibitor of Fas apoptotic signaling. Although trophoblast cells express Fas, susceptibility to Fas does not necessarily correlate with its expression. In this study, we demonstrate that Th-2 cytokines increase the resistance of trophoblast cells to Fas-mediated apoptosis either by inhibiting Fas expression or by inducing FLIP activation. This "trophoblast-cytokine-Fas/FasL triad" determines the ability of the Fas/FasL system to regulate trophoblast viability and, consequently, the success or failure of pregnancy.

The Fas/FasL system in reproduction: survival and apoptosis.

For centuries, the question of "whether there is life after death" has intrigued the mind of philosophers, and the same question fascinates researchers in the field of apoptosis today. The death of a cell is by no means the end of the story. On the contrary, growing evidence suggests that the clearance of apoptotic bodies by macrophages is an important regulatory component in tissue renewal. Without death by apoptosis, the life of reproductive tissues and their function would not be possible. The survival signals that counteract cell death also prepare the cells for apoptosis, and dead cells are important stimuli for tissue survival. The Fas/FasL system is an important mediator in apoptosis and is and excellent example of this apparently contradictory phenomenon.