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Defective Induction of the Transcription Factor Interferon-StimulatedGene Factor-3 and Interferon Insensitivity in Human Trophoblast Cells¹

^a Program in Development and Fetal Health, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, and the Departments of Molecular and Medical Genetics, and Obstetrics and Gynaecology, University of Toronto, Toronto, Ontario, Canada M5G 1X5 ^b Department of Anatomy, University of California, San Francisco, California 94143

During pregnancy, trophoblast cells of the placenta contact maternal immune cells and yet are protected from attack. One mechanism that may account for this is that trophoblasts show altered expression of major histocompatibility complex (MHC) antigens. The gene for human leukocyte antigen G (HLA-G), a nonclassical gene, is expressed at high levels in trophoblast. Unlike other MHC class I genes, the HLA-G gene lacks an interferon (IFN) response element. Moreover, we demonstrate here that IFN, which regulates classical MHC class I genes in other cell types, does not affect these genes in trophoblast, owing to inactivation of an IFN signaling pathway. Trophoblast cells (JEG-3 and JAR) were found to be selectively refractory to IFN. Specifically, although IFN induced the transcription factors STAT1, STAT2, and IFN regulatory factor-1, and a protective response against encephalomyocarditis virus, it failed to protect the cells from vesicular stomatitis virus, activate a transfected MHC class I gene promoter, and induce the transcription factor IFN-stimulated gene factor (ISGF)-3. The lack of ISGF3 DNA-binding activity apparently was due to diminished p48/ISGF3 subunit activity since ISGF3 DNA-binding activity and IFN induction of MHC class I promoter activity were reconstituted by p48/ISGF3 supplementation. These data indicate that a specific IFN signaling pathway is inactive in JEG-3 trophoblast cells because of altered activity of p48/ISGF3, and they suggest IFN insensitivity as a mechanism that may help promote feto-placental survival.

¹ This work was supported by grants from the Medical Research Council of Canada to J.C.C. (MT-12894) and the National Institutes of Health to Z.W. (HD 26732), and by the Office of Health and Environmental Research, U.S. Department of Energy (contract no. DE-AC03–76-SF01012). J.C.C. is a Scholar of the Medical Research Council of Canada.

² Correspondence: James C. Cross, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Room 880, 600 University Ave., Toronto, ON, Canada M5G 1X5. FAX: 416 586 8588; cross{at}mshri.on.ca

³ Current address: Hadassah-Hebrew University Medical Center, Department of Obstetrics and Gynecology, Hadassah Mount Scopus, P.O.B. 24035, Jerusalem, 91240 Israel.

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