A specific interferon (IFN)-stimulated response element of the distal HLA-G promoter binds IFN-regulatory factor 1 and mediates enhancement of this nonclassical class I gene by IFN-beta

Type I interferons display a broad range of immunomodulatory functions. Int erferon beta increases gene expression at the transcriptional level through binding of factors to the interferon-stimulated response element (ISRE) wi thin the promoters of interferon-inducible genes, such as HLA class I. Desp ite mutation of the class I ISRE sequence within the nonclassical HLA-G cla ss I gene promoter, we show that interferon beta enhances both transcriptio n and cell surface expression of HLA-G in trophoblasts and amniotic and thy mic epithelial cells that selectively express it in vivo. Deletion and muta genesis analysis of a putative interferon-regulatory factor (IRF)-1 binding site within the HLA-G promoter show that HLA-G transactivation is mediated through an ISRE sequence 746 base pairs upstream from ATG, which is distin ct from the interferon-responsive element described within proximal classic al class I gene promoters. Electrophoretic mobility shift analysis and supe rshift analysis further demonstrate that interferon-responsive transcriptio n factors, including IRF-1, specifically bind to the HLA-G ISRE. Our result s provide evidence that IRF-1 binding to a functional ISRE within the HLA-G promoter mediates interferon beta -induced expression of the HLA-G gene. T hese observations are of general interest considering the implication of HL A-G in mechanisms of immune escape involved in fetal-maternal tolerance and other immune privilege situations.