Opposing effects of interferon-α and interferon-γ on the expression of major histocompatibility complex class I chain-related A in tumors
Opposing effects of interferon-α and interferon-γ on the expression of major histocompatibility complex class I chain-related A in tumors
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DOI：
10.1111/j.1349-7006.2008.00791.x
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发表时间：
2008-06-01
期刊：
影响因子：
5.7
通讯作者：
Tian, Zhigang
中科院分区：
文献类型：
--
作者：
Zhang, Cai;Niu, Jiafeng;Tian, Zhigang
自然杀伤细胞是对病毒、细菌、某些寄生虫和肿瘤的先天抗性的重要组成部分。活化受体自然杀伤组2D（NKG 2D）在细胞毒性效应细胞消除肿瘤细胞中起关键作用。已经表明，抗肿瘤免疫应答的强度可能严重依赖于NKG 2D配体表面水平。因此，调节NKG 2D配体的表达以确保有效的肿瘤免疫监视和消除病原体感染的细胞是至关重要的。在本研究中，我们发现，干扰素（IFN）-α和IFN γ发挥相反的作用，对主要组织相容性复合物I类相关链A（云母）在人类肿瘤细胞的表达。IFN α促进肿瘤细胞中NKG 2D配体云母的表达，从而增强其对自然杀伤细胞溶解的敏感性。相反，IFN γ发挥相反的作用。IFN α通过增强云母启动子活性在转录水平上促进云母表达。IFN γ不仅在转录水平上调节云母表达，而且通过促进基质金属蛋白酶的蛋白水解切割在翻译后水平上调节MICA表达。需要进一步的研究来阐明精确的调控机制。参与NKG 2D配体诱导的途径可能代表了改善对癌症或感染的免疫应答的有希望的靶点。
Natural killer cells are an important component of innate resistance to viruses, bacteria, certain parasites, and tumors. The activating receptor natural killer group 2D (NKG2D) plays a critical role in the elimination of tumor cells by cytotoxic effector cells. It has been shown that the strength of an antitumor immune response might be critically dependent on NKG2D ligard surface levels. Thus, it is essential to regulate the expression of NKG2D ligands in order to ensure effective tumor immunosurveillance and the elimination of pathogen-infected cells. In the present study, we found that interferon (IFN)-alpha and IFN gamma exert opposing effects on major histocompatibility complex class I-related chain A (MICA) expression in human tumor cells. IFN alpha promotes expression of the NKG2D ligand MICA in tumor cells and therefore enhances their sensitivity to natural killer lysis. In contrast, IFN gamma exerts the opposite effect. IFN alpha promotes MICA expression at the level of transcription by augmenting MICA promoter activity. IFN gamma modulates MICA expression not only at the transcriptional level, but also at the post-translational level by promoting proteolytic cleavage by matrix metalloproteinases. Further study is needed to clarify the precise regulatory mechanisms. The pathways involved in NKG2D ligand induction might represent a promising target for improving immune responses to cancer or infections.