Synergistic induction of HLA class I expression by RelA and CIITA.
The major histocompatibility complex (MHC) class I genes are induced synergistically by interferons (IFN) and tumor necrosis factor (TNF), a response thought to involve the cooperative action of Rel/NF-kB and interferon regulatory factor (IRF) transcription factors. The IFN-gamma-inducible class II transcriptional activator (CIITA) has recently been shown to transactivate MHC class I as well as class II genes, and this investigation shows that CIITA synergizes strongly with RelA to stimulate HLA class I expression. The functional interaction of CIITA and RelA requires both promoter elements and the upstream Rel binding site and is not seen with a class II reporter. The promoter elements necessary for CIITA action are also required for induction by IFN-alpha. HLA-A and HLA-B loci respond differentially to IFNs, and we identify locus-specific differences in critical promoter elements in addition to known polymorphisms in the Rel and IRF binding sites. The HLA-A promoter is transactivated relatively poorly by CIITA and does not interact detectably with CREB proteins implicated in CIITA recruitment, but the synergism with RelA can compensate for this weakness. The present findings illustrate that multiple transcription factors cooperate to regulate class I expression and that their relative importance differs according to the locus and cell type examined. (Blood. 2000;95:3804-3808)
Girdlestone
J
J
Anatomy Department, MRC Centre for Immune Regulation, The Medical School, University of Birmingham, Birmingham, UK. girdlesj@bham.ac.uk
D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology*; D005805:Genes, MHC Class I; D015234:HLA-A Antigens / Q000235:genetics*; D015235:HLA-B Antigens / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology; D008668:Metallothionein / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism*; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D011994:Recombinant Proteins; D015534:Trans-Activators / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured
D015234:HLA-A Antigens; D015235:HLA-B Antigens; D007370:Interferon Type I; C083728:MHC class II transactivator protein; D016328:NF-kappa B; D009687:Nuclear Proteins; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D015534:Trans-Activators; D008668:Metallothionein