Han Y, Zhou Z H, Ransohoff R M
Department of Neuroscience, The Lerner Research Institute, Cleveland, OH 44195, USA.
J Immunol. 1999 Aug 1;163(3):1435-40.
Precise regulation of MHC class II gene expression is crucial for development and function of the immune system. Class II trans-activator (CIITA) has been shown to be required for constitutive and IFN-gamma-induced MHC class II transcription. TNF-alpha is commonly coexpressed with IFN-gamma during immune-mediated inflammatory responses and modulates IFN-gamma-stimulated MHC class II expression. The effect of TNF-alpha on MHC class II expression depends on cell type and cellular differentiation state. We show here that TNF-alpha suppresses IFN-gamma-induced CIITA mRNA accumulation, resulting in decreased MHC class II expression in human fibrosarcoma HT1080 cells. TNF-alpha also inhibits CIITA mRNA accumulation and protein expression in a tetracycline-regulated system without affecting promoter activity. CIITA mRNA, regulated by either IFN-gamma or tetracycline, was destabilized in the presence of TNF-alpha, suggesting that TNF-alpha utilizes a distinct mechanism to suppress MHC class II expression in HT1080 cells. Consistent with this interpretation, TNF-alpha blocked IFN-gamma-induced CIITA and MHC class II expression in mutant cells that are unresponsive to TGF-beta or IFN-beta. This is the first instance in which MHC class II expression is inhibited by destabilizing CIITA mRNA.
MHC II类基因表达的精确调控对于免疫系统的发育和功能至关重要。II类反式激活因子（CIITA）已被证明是组成型和IFN-γ诱导的MHC II类转录所必需的。在免疫介导的炎症反应中，TNF-α通常与IFN-γ共表达，并调节IFN-γ刺激的MHC II类表达。TNF-α对MHC II类表达的影响取决于细胞类型和细胞分化状态。我们在此表明，TNF-α抑制IFN-γ诱导的CIITA mRNA积累，导致人纤维肉瘤HT1080细胞中MHC II类表达降低。TNF-α在四环素调控系统中也抑制CIITA mRNA积累和蛋白表达，而不影响启动子活性。在TNF-α存在的情况下，受IFN-γ或四环素调控的CIITA mRNA不稳定，这表明TNF-α利用一种独特的机制来抑制HT1080细胞中MHC II类表达。与此解释一致，TNF-α在对TGF-β或IFN-β无反应的突变细胞中阻断IFN-γ诱导的CIITA和MHC II类表达。这是首次通过使CIITA mRNA不稳定来抑制MHC II类表达的实例。
