An epigenetic mechanism for high, synergistic expression of indoleamine 2,3-dioxygenase 1 (IDO1) by combined treatment with zebularine and IFN-γ: potential therapeutic use in autoimmune diseases.

Abstract	IDO1 can be induced by interferon gamma (IFN-γ) in multiple cell types. We have earlier described that the DNA methyltransferase inhibitor zebularine also induces IDO1 in several rat cell clones. We now describe a synergistic induction of IDO1 expression by IFN-γ and zebularine. To elucidate the mechanism of the IDO1 induction we have studied the methylation status in the promoter region of the IDO1 gene from both human monocytic THP-1 cells and H1D2 rat colon cancer cells. Interestingly, the IDO1 promoter is hypermethylated and IFN-γ is shown to induce a significant demethylation. The synergism in effect of zebularine and IFN-γ on IDO1 expression is paralleled by a similar synergistic effect on expression of two other IFN-γ-responsive genes, the transcription factors STAT1 and IRF1 with binding sites in the IDO1 promoter region. The demonstrated synergistic activation of IDO1 expression has implications in relation to therapeutic induction of immunosuppression in autoimmunity and chronic inflammation.
Authors	Zhong-Tian Xue, Hans-Olov Sjögren, Leif G Salford, Bengt Widegren
Journal	Molecular immunology (Mol Immunol) Vol. 51 Issue 2 Pg. 101-11 (Jun 2012) ISSN: 1872-9142 [Electronic] England
PMID	22424783 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright	Copyright © 2012 Elsevier Ltd. All rights reserved.
Chemical References	IRF1 protein, human Indoleamine-Pyrrole 2,3,-Dioxygenase Interferon Regulatory Factor-1 STAT1 Transcription Factor Cytidine pyrimidin-2-one beta-ribofuranoside Interferon-gamma
Topics	Animals Autoimmune Diseases (genetics) Cells, Cultured Cytidine (administration & dosage, analogs & derivatives) DNA Methylation Drug Synergism Epigenesis, Genetic (genetics) Gene Expression (drug effects) Gene Expression Regulation (drug effects) Humans Indoleamine-Pyrrole 2,3,-Dioxygenase (biosynthesis, genetics) Interferon Regulatory Factor-1 (biosynthesis, genetics) Interferon-gamma (administration & dosage) Promoter Regions, Genetic Rats Real-Time Polymerase Chain Reaction Reverse Transcriptase Polymerase Chain Reaction STAT1 Transcription Factor (biosynthesis, genetics)

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