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International Immunology Advance Access originally published online on October 1, 2008
International Immunology 2008 20(11):1457-1466; doi:10.1093/intimm/dxn103
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© The Japanese Society for Immunology. 2008. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Methylation of CIITA promoter IV causes loss of HLA-II inducibility by IFN-{gamma} in promyelocytic cells

Andrea De Lerma Barbaro1, Alessandro De Ambrosis2, Barbara Banelli3, Giuseppina Li Pira4, Ottavia Aresu5, Massimo Romani3, Silvano Ferrini6 and Roberto S. Accolla1

1 Department of Clinical and Biological Sciences, Unit of General Pathology and Immunology, School of Medicine, Università of Insubria, Varese, Italy
2 Laboratory of Traslational Pediatric Oncology, Istituto Nazionale per la Ricerca sul Cancro (Istituto Scientifico Tumori, IST) Genova, Italy
3 Laboratory of Tumor Genetics, Istituto Nazionale per la Ricerca sul Cancro (Istituto Scientifico Tumori, IST) Genova, Italy
4 Laboratory of Cellular Immunology, Advanced Biotechnology Center, Genova, Italy
5 Banca Biologica e Cell Factory, Istituto Nazionale per la Ricerca sul Cancro (IST) Genova, Italy
6 Laboratory of Immunological Therapy, Istituto Nazionale per la Ricerca sul Cancro (IST) Genova, Italy

Correspondence to: A. De Lerma Barbaro; E-mail: a.delermabarbaro{at}uninsubria.it

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.

Keywords: 5-azacytidine, gene regulation, MHC class II, transcription factors

Transmitting editor: L. Moretta

Received 14 May 2008, accepted 22 August 2008.


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