期刊
INTERNATIONAL IMMUNOLOGY
卷 20, 期 11, 页码 1457-1466出版社
OXFORD UNIV PRESS
DOI: 10.1093/intimm/dxn103
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资金
- Italian National Institute of Health (ISS)
- National Research Project on AIDS [40F.1, 45G.1]
- Fondi di Ateneo per la Ricerca 2006-2007
- Department of Clinical and Biological Sciences, University of Insubria
- Italian Ministry of Health, Ordinary Project
- Associazione Italiana per la Ricerca sul Cancro
The human promyelocytic cell line THP-1 expresses high level of HLA class II (HLA-II) molecules after IFN-gamma treatment. Here, we report a variant of THP-1 that does not express HLA-II after IFN-gamma. The variant's HLA-II phenotype is constant over time in culture and it is not related to a defective IFN-gamma-signalling pathway. Transfection of CIITA, the HLA-II transcriptional activator, under the control of a cytomegalovirus promoter rescues high level of HLA-DR surface expression in the variant indicating that the biosynthetic block resides in the expression of CIITA and not in the CIITA-dependent transactivation of the HLA-II promoters. Treatment of the variant with 5-azacytidine (5-aza), which inhibits CpG methylation, restores inducibility of HLA-II by IFN-gamma both at transcriptional and phenotypic level and antigen presenting and processing function of the variant. DNA studies demonstrate that the molecular defect of the THP-1 variant originates from the methylation of the CIITA promoter IV. Furthermore, treatment with 5-aza produces a substantial demethylation of CIITA promoter IV and a significant increase of IFN-gamma-dependent HLA-II expression in another myelomonocytic cell line, U937. Therefore hyper-methylation of CIITA promoter IV may be a relevant mechanism of epigenetic control preventing HLA-II IFN-gamma inducibility in the myelomonocytic cell lineage.
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