Indoleamine 2,3-Dioxygenase, an Immunomodulatory Protein, Is Suppressed by (-)-Epigallocatechin-3-gallate via Blocking of γ-Interferon-Induced JAK-PKC-δ-STAT1 Signaling in Human Oral Cancer Cells
Indoleamine 2,3-Dioxygenase, an Immunomodulatory Protein, Is Suppressed by (-)-Epigallocatechin-3-gallate via Blocking of γ-Interferon-Induced JAK-PKC-δ-STAT1 Signaling in Human Oral Cancer Cells
复制标题
DOI：
10.1021/jf903377e
复制
发表时间：
2010-01-27
影响因子：
6.1
通讯作者：
Way, Tzong-Der
中科院分区：
文献类型：
--
作者：
Cheng, Chieh-Wen;Shieh, Po-Chuen;Way, Tzong-Der
免疫逃逸是癌症进展的一个特征，但其潜在的分子机制仍知之甚少。一种免疫调节蛋白，吲哚胺2,3 - 双加氧酶（IDO），可由γ - 干扰素（IFN - γ）在几种免疫细胞中诱导产生；这些细胞在癌细胞微环境中被观察到，并可增强免疫逃逸。先前的研究表明，IDO在肿瘤形成过程中表达，并与癌细胞的免疫耐受相关。通过局部降解色氨酸，IDO抑制T淋巴细胞的增殖并诱导T细胞凋亡，从而导致T细胞反应受到抑制。在本研究中，（ - ） - 表没食子儿茶素 - 3 - 没食子酸酯（EGCG），绿茶的主要成分，被发现可显著抑制人口腔癌细胞系中IDO的表达。EGCG在转录水平抑制IDO的诱导。研究发现STAT1的激活在IFN - γ调节IDO表达中起重要作用。研究结果表明，在IFN - γ刺激的人口腔癌细胞中，EGCG可抑制STAT1向细胞核的转位。此外，EGCG还可抑制STAT1的酪氨酸和丝氨酸磷酸化。而且，在IFN - γ刺激的人口腔癌细胞中，EGCG还抑制PKC - δ、JAK - 1和JAK - 2的磷酸化，这些是STAT1激活的上游事件。这些数据表明，EGCG通过阻断IFN - γ诱导的JAK - PKC - δ - STAT1信号通路来抑制IDO的表达。这项研究表明，EGCG是一种用于免疫和靶向治疗的潜在药物，可通过增强抗肿瘤免疫力来提高癌症治疗效果。
Immune escape is a characteristic of cancer progression, but its underlying molecular mechanism is still poorly understood. An immunomodulatory protein, indoleamide 2,3-dioxygenase (IDO), is induced by gamma-interferon (IFN-gamma) in several immune cells; those cells are observed in cancer cell microenvironment and can enhance immune escape. Previous studies show that IDO is expressed in the process of tumor formation and associated with cancer cell immune tolerance. By locally degrading tryptophan, IDO inhibits the proliferation of T lymphocytes and induces T cell apoptosis, leading to suppression of T cell response. In this study, (-)-epigallocatechin-3-gallate (EGCG), the major constituent of green tea, is found to significantly inhibit the expression of IDO in human oral cancer cell lines. EGCG suppresses the induction of IDO at transcriptional level. Activation of STAT1 is discovered to play an important role in regulating IDO expression by IFN-gamma. The study results demonstrate that EGCG can inhibit translocation of STAT1 into nucleus in IFN-gamma-stimulated human oral cancer cells. In addition, both tyrosine. and serine phosphorylation of STAT1 are to be suppressed by EGCG. Moreover, phosphorylation of PKC-delta, JAK-1, and JAK-2, which are the upstream event for the activation of STAT1, are also inhibited by EGCG in IFN-gamma-stimulated human oral cancer cells. These data show that EGCG inhibited IDO expression by blocking the IFN-gamma-induced JAK-PKC-delta-STAT1 signaling pathway. This study indicates that EGCG is a potential drug for immune and target therapy to enhance cancer therapy by increasing antitumor immunity.