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

作者：Xue Zhong Tian; Sjogren Hans Olov; Salford Leif G; Widegren Bengt^*

来源：Molecular Immunology, 2012, 51(2): 101-111.

DOI：10.1016/j.molimm.2012.01.006

• IDO1 gene promoter
• Human and rat
• DNA methylation
• Zebularine
• IFN-gamma
• Transcription factors

IDO1 can be induced by interferon gamma (IFN-gamma) 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-gamma 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 H1 D2 rat colon cancer cells. Interestingly, the IDO1 promoter is hypermethylated and IFN-gamma is shown to induce a significant demethylation. The synergism in effect of zebularine and IFN-gamma on IDO1 expression is paralleled by a similar synergistic effect on expression of two other IFN-gamma-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.

• 出版日期2012-6