Polymorphism in the Y box controls level of cytokine-mediated expression of HLA-DRB1 genes.
The HLA class II molecules play an important role in immune response. The quality of immune response is dependent not only on the polymorphisms in the class II molecules, but also on the level of their cell-surface expression. In fact, it has been demonstrated that differences in the level of expression of DRB1 and DRB3 genes restricted and activated distinct CD4+ T lymphocytes. We and others have previously described allelic polymorphisms in the upstream regulatory regions of DRB genes, which affected DNA-protein interactions and resulted in significantly different promoter strengths. We showed that polymorphisms in both the X1 and Y box motifs affect level of constitutive expression of DRB1 genes in the DR1, DR51 and DR53 haplotype groups. In the present study, we examined the effect polymorphisms in the X1 box and the Y box on the cytokine (interferon-gamma (IFNgamma), tumor necrosis factor-alpha (TNFalpha) and granulocyte macrophage-colony-stimulating factor (GM-CSF))-mediated transcriptional activities of DRB1 promoters in these, i.e. DR1, DR51 and DR53, haplotype groups. The results demonstrate that the polymorphism in the X1 box does not affect cytokine-mediated strength of DRB1 gene promoters. In contrast, the polymorphism in the Y box, which affects the inverted CCAAT sequence, plays a dominant role on the cytokine-mediated transcriptional activity of DRB1 promoters.
Sindwani
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Department of Pathology and Molecular Medicine McMaster University, Hamilton, Ontario, Canada.
Singal
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DP
D001483:Base Sequence; D002478:Cells, Cultured; D015500:Chloramphenicol O-Acetyltransferase / Q000032:analysis; D017124:Conserved Sequence; D016207:Cytokines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006684:HLA-DR Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006239:Haplotypes; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D016207:Cytokines; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D015500:Chloramphenicol O-Acetyltransferase