Molecular mechanisms controlling constitutive and IFN-gamma-inducible HLA-G expression in various cell types.
HLA-G molecule is thought to play a major role in down-regulating the maternal immune response by inhibiting NK and T cell cytolytic activities. We examined the molecular regulatory mechanisms that may control the restricted expression pattern of the HLA-G gene. We first analyzed protein interactions between nuclear extracts from the HLA-G-positive JEG-3 choriocarcinoma and the HLA-G-negative NK-like YT2C2 cell lines to a 244 bp regulatory element located 1.2 kb from the HLA-G gene, previously shown to direct HLA-G expression in transgenic mouse placenta. This allowed characterization of cell-specific DNA-protein interactions that could account for differential cell-specific expression of the HLA-G gene. In particular two DNA-protein complexes were exclusively observed in YT2C2, suggesting that this HLA-G regulatory element is a target for putative cell-specific repressor factors. We further mapped nuclear factor binding sites to a 70 bp fragment in the upstream region of the regulatory element. We then investigated the effect of IFN-gamma on HLA-G gene expression. HLA-G cell surface expression was enhanced by IFN-gamma treatment in JEG-3 and U937 cell lines and peripheral blood monocytes while no effect was observed in tera-2 teratocarcinoma cell line. HLA-G transcriptional activity was increased only in JEG-3 and U937 cell lines. Activity of the 1.4-kb HLA-G promoter region was unchanged after IFN-gamma treatment in JEG-3 and Tera-2. These results suggest that both post-transcriptional and transcriptional mechanisms implicating IFN-responsive regulatory sequences outside the 1.4 kb-region are involved in IFN-gamma gene activation of the HLA-G gene.
Lefebvre
S
S
CEA, Service de Recherches en Hémato-Immunologie, DSV/DRM, Hôpital Saint-Louis, Centre Hayem 1, Paris, France.
Moreau
P
P
Guiard
V
V
Ibrahim
E C
EC
Adrian-Cabestre
F
F
Menier
C
C
Dausset
J
J
Carosella
E D
ED
Paul
P
P
D015870:Gene Expression; D006680:HLA Antigens / Q000096:biosynthesis / Q000235:genetics*; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology* / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012045:Regulatory Sequences, Nucleic Acid; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D020298:U937 Cells; D015854:Up-Regulation
D006680:HLA Antigens; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I; D009687:Nuclear Proteins; D007371:Interferon-gamma