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. Interferon beta increases gene expression at the transcriptional level through binding of factors to the interferon-stimulated response element (ISRE) within the promoters of interferon-inducible genes, such as HLA class I. Despite mutation of the class I ISRE sequence within the nonclassical HLA-G class I gene promoter, we show that interferon beta enhances both transcription and cell surface expression of HLA-G in trophoblasts and amniotic and thymic epithelial cells that selectively express it in vivo. Deletion and mutagenesis 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 distinct from the interferon-responsive element described within proximal classical class I gene promoters. Electrophoretic mobility shift analysis and supershift analysis further demonstrate that interferon-responsive transcription factors, including IRF-1, specifically bind to the HLA-G ISRE. Our results 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. These observations are of general interest considering the implication of HLA-G in mechanisms of immune escape involved in fetal-maternal tolerance and other immune privilege situations.
Lefebvre
S
S
Service de Recherches en Hémato-Immunologie, Comissariat à l' Energie Atomique, DSV/DRM, Institut d'Hématologie, Hôpital Saint-Louis, Centre Hayem 1, avenue Claude Vellefaux, 75475 Paris cedex 10, France.
Berrih-Aknin
S
S
Adrian
F
F
Moreau
P
P
Poea
S
S
Gourand
L
L
Dausset
J
J
Carosella
E D
ED
Paul
P
P
D000650:Amnion / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D005805:Genes, MHC Class I; D006680:HLA Antigens / Q000235:genetics*; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D050856:Interferon Regulatory Factor-1; D016899:Interferon-beta / Q000494:pharmacology*; D010750:Phosphoproteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis; D020218:Response Elements; D015533:Transcriptional Activation; D014327:Trophoblasts / Q000378:metabolism; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D006680:HLA Antigens; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D010750:Phosphoproteins; D012333:RNA, Messenger; D016899:Interferon-beta