The DOI matches its Crossref record; 71 of the 71 references it cites were found in a registry or an index.
Differential Regulation and Function of the Fas/Fas Ligand System in Human Trophoblast Cells1
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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In the citing paper
“Similar observations with increased expression of Th1 cytokines such as IL-2, TNF, IFN-γ and decreased Th2 cytokines such as IL-6 and TGF-β have been reported by others [31]”
From Submicroscopic infection of placenta by Plasmodium produces Th1/Th2 cytokine imbalance, inflammation and hypoxia in women from north-west Colombia (2014) · cites this paper as [31]
In the citing paper
“In in vitro studies with cell models and placental tissue explants stimulated with pro-inflammatory cytokines, the expression of Fas and FasL was high and similar to the results reported here [31].”
From Submicroscopic infection of placenta by Plasmodium produces Th1/Th2 cytokine imbalance, inflammation and hypoxia in women from north-west Colombia (2014) · cites this paper as [31]
Citations
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Inhibition of death receptor signals by cellular FLIP
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Implantation and the Survival of Early Pregnancy
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The Role of c-FLIP in Modulation of CD95-induced Apoptosis
Scaffidi, C., Schmitz, I., Krammer, P. H., & Peter, M. E. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.3.1541 · Cited by 819
Research works printed but not linked: 2
- 1998, Macrophage-derived growth factors regulate FasL expression in endometrial stromal cells, Mol Hum Reprod, 5, 642
- 1999, Macrophage-derived growth factors modulate Fas ligand expression in cultured trophoblast cells: a role in implantation, Am J Reprod Immunol, 41, 395
Cited by
Sorted by citations
Macrophages and Apoptotic Cell Clearance During Pregnancy
Abrahams, V. M., Kim, Y. M., Chavez, S. L., Romero, R. J., & Mor, G. (2004) · American Journal of Reproductive Immunology · doi:10.1111/j.1600-0897.2004.00156.x · Cited by 361
Self-citationApoptosis and its role in the trophoblast
Huppertz, B., Kadyrov, M., & Kingdom, J. C. (2006) · American Journal of Obstetrics and Gynecology · doi:10.1016/j.ajog.2005.07.039 · Cited by 343
The Role of Apoptosis in the Regulation of Trophoblast Survival and Differentiation during Pregnancy
Chavez, S. L., Abrahams, V. M., & Mor, G. (2005) · Endocrine Reviews · doi:10.1210/er.2005-0003 · Cited by 310
Self-citationDivergent Trophoblast Responses to Bacterial Products Mediated by TLRs
Abrahams, V. M., Aldo, P. B., Kim, Y. M., Chavez, S. L., Chaiworapongsa, T., Romero, R. J., & Mor, G. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.173.7.4286 · Cited by 278
Self-citationApoptosis in the Trophoblast—Role of Apoptosis in Placental Morphogenesis
Huppertz, B., & Kingdom, J. C. P. (2004) · Journal of the Society for Gynecologic Investigation · doi:10.1016/j.jsgi.2004.06.002 · Cited by 262
Metadata
- Authors
- Aschkenazi, S., Straszewski, S., Verwer, K. M. A., Foellmer, H., Rutherford, T., & Mor, G.
- Affiliations
- Yale University (US)
- Corresponding author
- 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
- 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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