Cited by 161Reproductive System and PregnancyCell death mechanisms and regulationPregnancy and preeclampsia studies

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Differential Regulation and Function of the Fas/Fas Ligand System in Human Trophoblast Cells1

Aschkenazi, Sarit, Straszewski, Shawn, Verwer, Karlijn M.A., Foellmer, Harald, Rutherford, Thomas, Mor, Gil·2002·Biology of Reproduction

DOI 10.1095/biolreprod66.6.1853

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Abstract

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.

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Authors: Aschkenazi, S., Straszewski, S., Verwer, K. M. A., Foellmer, H., Rutherford, T., & Mor, G.
Affiliations: Yale University (US)
Corresponding author: Mor, Gil
ORCID: Aschkenazi, Sarit
Rutherford, Thomas
Mor, Gil
Venue: Biology of Reproduction
Publisher: Oxford University Press (OUP)
Published: 2002-06-01
Volume: 66
Issue: 6
Pages: 1853-1861
ISSN: 0006-3363 (ISSN-L)
1529-7268
DOI: 10.1095/biolreprod66.6.1853
OpenAlex: W2142773418
Cited by: 161
References: 71
Citations by year: 2026: 2 · 2025: 2 · 2024: 3 · 2023: 1 · 2022: 4 · 2021: 8 · 2020: 7 · 2019: 5 · 2018: 6 · 2017: 2 · 2016: 6 · 2015: 2 · 2014: 8 · 2013: 8 · 2012: 6
FWCI: 3.39
Type: journal article
Language: en
Open access: closed
Locations: Biology of Reproduction (publishedVersion)
PubMed (publishedVersion)
BioOne Complete (BioOne) (submittedVersion)
Funders: National Cancer Institute (R01CA092435, R01 CA92435-01)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01 HD37137-01A2, R01HD037137)
Topics: Life Sciences › Immunology and Microbiology › Immunology › Reproductive System and Pregnancy
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy and preeclampsia studies
Keywords: Fas/Fas ligand, trophoblast, apoptosis, Th1 cytokines, Th2 cytokines, interferon-gamma, TNF-α, interleukin-6, IL-10, FLICE-like inhibitory protein, Fas expression, implantation, pregnancy outcomes
MeSH terms: Carrier Proteins, Cells, Cultured, Female, Gene Expression Regulation, Gestational Age, Humans, Interferon-gamma, Membrane Glycoproteins, Pregnancy, Trophoblasts, Tumor Necrosis Factor-alpha, Blotting, Western, Interleukin-6, Cytokines, Interleukin-10, Apoptosis, Th1 Cells, Th2 Cells, fas Receptor, Reverse Transcriptase Polymerase Chain Reaction, Intracellular Signaling Peptides and Proteins, Fas Ligand Protein, CASP8 and FADD-Like Apoptosis Regulating Protein

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Differential Regulation and Function of the Fas/Fas Ligand System in Human Trophoblast Cells1

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