Tipifarnib-mediated suppression of T-bet-dependent signaling pathways.
Tipifarnib-mediated suppression of T-bet-dependent signaling pathways.
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DOI：
10.1007/s00262-011-1109-0
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发表时间：
2012-04
期刊：
影响因子：
--
通讯作者：
Epling-Burnette P
中科院分区：
文献类型：
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作者：
Bai F;Villagra AV;Zou J;Painter JS;Connolly K;Blaskovich MA;Sokol L;Sebti S;Djeu JY;Loughran TP;Wei S;Sotomayor E;Epling-Burnette P
大颗粒淋巴细胞白血病（LGL）是一种慢性淋巴细胞增生性疾病，T-bet [T-box transcription factor 21 gene（tbx 21）]过表达可能起致病作用。T-bet协调成熟外周T细胞分化为产生干扰素-γ（IFN-γ）和肿瘤坏死因子-α的CD 4 + T辅助细胞I型（Th 1）和CD 8 + T细胞毒性细胞，这些细胞是抗病毒应答所必需的。当IL-12由抗原呈递细胞产生时，T-bet表达被诱导，导致ifng基因转录的直接刺激，同时作为IL 4基因的转录抑制物，其随后导致Th 1优势和辅助性T细胞2型分化阻断。此外，T-bet已被证明可调节ifng启动子和增强子的组蛋白乙酰化，以松开凝聚的DNA，为其他转录因子结合创造更大的可及性，这进一步放大IFNγ的产生。我们发现，用法尼基转移酶抑制剂tipifarnib治疗减少了LGL白血病患者T细胞中的Th 1细胞因子，并阻断了健康供体T细胞中的T-bet蛋白表达和IL-12反应性。抑制的机制是基于ifng基因的组蛋白乙酰化的调节，其最终导致Th 1阻断。
Large granular lymphocyte (LGL) leukemia is a chronic lymphoproliferative disease in which T-bet [T-box transcription factor 21 gene (tbx21)] overexpression may play a pathogenic role. T-bet orchestrates the differentiation of mature peripheral T-cells into interferon-γ (IFN-γ) and tumor necrosis factor-α producing CD4+ T-helper type I (Th1) and CD8+ T cytotoxic cells that are necessary for antiviral responses. When IL-12 is produced by antigen–presenting cells, T-bet expression is induced, causing direct stimulation of ifng gene transcription while simultaneously acting as a transcriptional repressor of the IL4 gene, which then leads to Th1 dominance and T-helper type 2 differentiation blockade. Additionally, T-bet has been shown to regulate histone acetylation of the ifng promoter and enhancer to loosen condensed DNA, creating greater accessibility for other transcription factor binding, which further amplifies IFNγ production. We found that treatment with a farnesyltransferase inhibitor tipifarnib reduced Th1 cytokines in LGL leukemia patient T-cells and blocked T-bet protein expression and IL-12 responsiveness in T-cells from healthy donors. The mechanism of suppression was based on modulation of histone acetylation of the ifng gene, which culminated in Th1 blockade.