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-Inducible Gene Expression in Mouse Trophoblast Cells1
* Columbia University, New York, NY 10032;
Roswell Park Cancer Institute, Buffalo, NY 14263; and
Department of Obstetrics and Gynecology, Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642
Trophoblast cells are the first cells to differentiate from the developing mammalian embryo, and they subsequently form the blastocyst-derived component of the placenta. IFN-
plays critical roles in activating innate and adaptive immunity, as well as apoptosis. In mice, IFN- is produced in the pregnant uterus, and is essential for formation of the decidual layer of the placenta and remodeling of the uterine vasculature. Responses of mouse trophoblast cells to IFN- appear to be selective, for IFN- activates MHC class I expression and enhances phagocytosis, but fails to activate either MHC class II expression or apoptosis in these cells. To investigate the molecular basis for the selective IFN- responsiveness of mouse trophoblast cells, IFN--inducible gene expression was examined in the trophoblast cell lines SM9 and M-11, trophoblast stem cells, and trophoblast stem cell-derived giant cells. IFN--inducible expression of multiple genes, including IFN regulatory factor-1 (IRF-1), was significantly reduced in trophoblast cells compared with fibroblast cells. Decreased IRF-1 mRNA expression in trophoblast cells was due to a reduced rate of IRF-1 transcription relative to fibroblast cells. However, no impairment of STAT-1 tyrosine phosphorylation or DNA-binding capacity was observed in IFN--treated mouse trophoblast cells. Importantly, histone deacetylase (HDAC) inhibitors significantly enhanced IFN--inducible gene expression in trophoblast cells, but not fibroblasts. Our collective studies demonstrate that IFN--inducible gene expression is repressed in mouse trophoblast cells by HDACs. We propose that HDAC-mediated inhibition of IFN--inducible gene expression in mouse trophoblast cells may contribute to successful pregnancy by preventing activation of IFN- responses that might otherwise facilitate the destruction of the placenta.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from the National Institutes of Health (R01 HD37464) and the Roswell Park Cancer Institute Alliance, and Roswell Park Cancer Center Support Grant P30 CA 16056. J.C.C. was supported by National Cancer Institute Predoctoral Training Grant 55640201.
2 Address correspondence and reprint requests to Dr. Shawn P. Murphy, Departments of Obstetrics and Gynecology, and Microbiology and Immunology, University of Rochester, 601 Elmwood Avenue, Box 668, Rochester, NY 14642. E-mail address: shawn_murphy{at}urmc.rochester.edu
3 Abbreviations used in this paper: TBC, trophoblast cell; ChIP, chromatin immunoprecipitation; GAS, IFN--activating sequence; GBP, guanylate-binding protein; GD, gestation day; H3, histone 3; HAT, histone acetyltransferase; HDAC, histone deacetylase; HSC70, heat shock cognate 70; IP-10, IFN--inducible protein-10; IRF-1, IFN regulatory factor-1; LMP, low molecular protein; MIG, monokine induced by IFN-; mIRF-1, murine IRF-1; pSTAT-1, phosphorylated dimers of STAT-1; PTP, protein tyrosine phosphatase; qRT-PCR, quantitative RT-PCR; TS, trophoblast stem; TSA, trichostatin A; USF-1, upstream stimulatory factor-1; WB, Western blot; WCE, whole-cell extract; pIV, promoter IV; HDACi, HDAC inhibitor.
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