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Dampening of IFN--Inducible Gene Expression in Human Choriocarcinoma Cells Is Due to Phosphatase-Mediated Inhibition of the JAK/STAT-1 Pathway¹

Jason C. Choi^*, Renae Holtz^*, Margaret G. Petroff, Nadia Alfaidy and Shawn P. Murphy^2,

^* Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263; Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160; Institut National de la Santé et de la Recherche Médicale, Equipe Mixte Institut National de la Santé et de la Recherche Médicale 01-05, Département Réponse et Dyamique Cellulaires, Laboratoire d’Angiogenése, Commissariat a‘ l’Energie Atomique et Universite' Joseph Fourier, Grenoble, France; and Departments of Obstetrics and Gynecology, Microbiology and Immunology, University of Rochester, Rochester, NY 14642

Trophoblast cells (TBCs) form the blastocyst-derived component of the placenta and play essential roles in fetal maintenance. The proinflammatory cytokine IFN- plays a central role in activating cellular immunity, controlling cell proliferation, and inducing apoptosis. IFN- is secreted by uterine NK cells in the placenta during pregnancy and in mice is required for proper formation of the decidual layer and remodeling of the uterine vasculature. Despite the presence of IFN- in the placenta, TBCs do not express either MHC class Ia or class II Ags, and are resistant to IFN--mediated apoptosis. In this study, we demonstrate that IFN--induced expression of multiple genes is significantly reduced in human trophoblast-derived choriocarcinoma cells relative to HeLa epithelial or fibroblast cells. These results prompted us to investigate the integrity of the JAK/STAT-1 pathway in these cells. Choriocarcinoma cells and HeLa cells express comparable levels of the IFN- receptor. However, tyrosine phosphorylation of JAK-2 is compromised in IFN--treated choriocarcinoma cells. Moreover, phosphorylation of STAT-1 at tyrosine 701 is substantially reduced in both IFN--treated human choriocarcinoma and primary TBCs compared with HeLa cells or primary foreskin fibroblasts. A corresponding reduction of both IFN regulatory factor 1 mRNA and protein expression was observed in IFN--treated TBCs. Treatment of choriocarcinoma cells with the tyrosine phosphatase inhibitor pervanadate significantly enhanced IFN--inducible JAK and STAT-1 tyrosine phosphorylation and select IFN--inducible gene expression. We propose that phosphatase-mediated suppression of IFN- signaling in TBCs contributes to fetal maintenance by inhibiting expression of genes that could be detrimental to successful pregnancy.

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), the Roswell Park Cancer Institute Alliance, and the 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; GBP, guanylate-binding protein; IRF-1, IFN regulatory factor 1; USF-1, upstream stimulatory factor 1; cTBC, cytotrophoblast cell; WCE, whole cell extract; PTP, protein tyrosine phosphatase; PV, pervanadate; PIAS, protein inhibitor of activated STAT; SOCS-1, suppressors of cytokine signaling 1; ROS, reactive oxygen species; TcPTP, T cell protein tyrosine phosphatase; SHP, Src homology region 2 domain-containing phosphatase.

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