Direct role of NF-kappaB activation in Toll-like receptor-triggered HLA-DRA expression.
Microbial components, such as DNA containing immunostimulatory CpG motifs (CpG-DNA) and lipopolysaccharides (LPS), elicit the cell surface expression of MHC class II (MHC-II) through Toll-like receptor (TLR)/IL-1R. Here, we show that CpG-DNA and LPS induce expression of the HLA-DRA in the human B cell line, RPMI 8226. Ectopic expression of the dominant negative mutant of CIITA and RNA interference targeting the CIITA gene indicate that CIITA activation is not enough for the maximal MHC-II expression induced by CpG-DNA and LPS. Additionally, nuclear factor (NF)-kappaB activation is required for the CpG-DNA-activated and LPS-activated HLA-DRA expression, whereas IFN-gamma-induced MHC-II expression depends on CIITA rather than on NF-kappaB. Comprehensive mutant analyses, electrophoretic mobility shift assays and chromatin immunoprecipitation assays, reveal that the functional interaction of NF-kappaB with the promoter element is necessary for the TLR-mediated HLA-DRA induction by CpG-DNA and LPS. This novel mechanism provides the regulation of MHC-II gene expression with complexity and functional diversity.
Lee
Keun-Wook
KW
Center for Medical Science Research, College of Medicine, Hallym University, Chuncheon Gangwon-do, Korea.
Lee
Younghee
Y
Kim
Doo-Sik
DS
Kwon
Hyung-Joo
HJ
D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology; D001402:B-Lymphocytes / Q000378:metabolism; D001483:Base Sequence; D002460:Cell Line; D004269:DNA, Bacterial / Q000494:pharmacology; D006684:HLA-DR Antigens / Q000235:genetics*; D059805:HLA-DR alpha-Chains; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008969:Molecular Sequence Data; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B / Q000502:physiology*; D009687:Nuclear Proteins / Q000502:physiology; D011401:Promoter Regions, Genetic; D048029:TNF Receptor-Associated Factor 6 / Q000502:physiology; D051193:Toll-Like Receptors / Q000502:physiology*; D015534:Trans-Activators / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; C472452:CpG-DNA, E coli; D004269:DNA, Bacterial; D006684:HLA-DR Antigens; D059805:HLA-DR alpha-Chains; D008070:Lipopolysaccharides; C083728:MHC class II transactivator protein; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D009687:Nuclear Proteins; D048029:TNF Receptor-Associated Factor 6; D051193:Toll-Like Receptors; D015534:Trans-Activators; D007371:Interferon-gamma