Defective induction of the transcription factor interferon-stimulated genefactor-3 and interferon alpha insensitivity in human trophoblast cells

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