Synergistic transcriptional activation of indoleamine dioxygenase by IFN-γ and tumor necrosis factor-α
Synergistic transcriptional activation of indoleamine dioxygenase by IFN-γ and tumor necrosis factor-α
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DOI：
10.1089/107999003322277829
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发表时间：
2003-08-01
影响因子：
2.3
通讯作者：
Carlin, JM
中科院分区：
文献类型：
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作者：
Robinson, CM;Shirey, KA;Carlin, JM
干扰素-γ（IFN-γ）诱导的吲哚胺2，3-双加氧酶（IDO）活性通过催化L-色氨酸的吲哚环的氧化裂解和消耗必需氨基酸库来抑制易感细胞内病原体的生长。肿瘤坏死因子-α（TNF-α）在人上皮细胞中在转录水平上协同增强IFN-γ诱导的IDO活性。本研究的目的是表征负责响应IFN-γ和TNF-α的协同基因表达的分子机制。研究发现，IFN-γ诱导的机制，如Stall与γ激活序列（GAS）的结合和IFN调节因子-1（IRF-1）与IFN刺激的应答元件（ISRE）的结合，在用IFN和TNF-α处理后更高度活化。这种增强的信号转导可能是由于联合细胞因子刺激后IFN-γ受体（IFNGR）表达的增加，并且可能有助于协同作用。此外，使用控制拷贝数的质粒报告系统研究了与Stat 1形成复合物的第三个先前未表征的GAS元件的贡献。当GAS-3序列被包括在调控区中时，基因表达相对于含有突变的GAS-3的区域显著增加。这表明GAS-3具有转录活性，并有助于IFN-γ诱导的IDO基因调控。
Interferon-gamma (IFN-gamma)-induced indoleamine 2,3-dioxygenase (IDO) activity inhibits the growth of susceptible intracellular pathogens by catalyzing the oxidative cleavage of the indole ring of L-tryptophan and depleting pools of the essential amino acid. Tumor necrosis factor-alpha (TNF-alpha) synergistically enhances the IDO activity induced by IFN-gamma at the level of transcription in human epithelial cells. The purpose of this study was to characterize the molecular mechanisms responsible for synergistic gene expression in response to IFN-gamma and TNF-alpha. It was found that IFN-gamma-induced mechanisms, such as the binding of Stall to gamma activation sequences (GAS) and IFN regulatory factor-1 (IRF-1) to IFN-stimulated response elements (ISREs), are more highly activated following treatment with IFN and TNF-alpha. This enhanced signal transduction may be due to the increase in IFN-gamma receptor (IFNGR) expression following combined cytokine stimulation and is a likely contributor to the synergy. Additionally, the contribution of a third previously uncharacterized GAS element that forms a complex with Stat1 was investigated using a plasmid reporter system that controls for copy number. When the GAS-3 sequence was included in the regulatory region, gene expression was significantly increased relative to a region containing the mutated GAS-3. This suggests that GAS-3 is transcriptionally active and contributes to IFN-gamma-induced regulation of the IDO gene.