IFN Regulatory Factor-1 Regulates IFN-γ-Dependent Cathepsin S Expression1
IFN Regulatory Factor-1 Regulates IFN-γ-Dependent Cathepsin S Expression1
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DOI：
10.4049/jimmunol.168.9.4488
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发表时间：
2002-05
期刊：
影响因子：
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通讯作者：
K. Storm van's Gravesande;M. Layne;Qiang Ye;Louis Le;R. Baron;M. Perrella;L. Santambrogio;E. Silverman;R. Riese
中科院分区：
文献类型：
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作者：
K. Storm van's Gravesande;M. Layne;Qiang Ye;Louis Le;R. Baron;M. Perrella;L. Santambrogio;E. Silverman;R. Riese
组织蛋白酶S是一种半胱氨酸蛋白酶，具有强大的内蛋白水解活性和广泛的pH谱。组织蛋白酶S活性对于B细胞和树突状细胞内MHC ii类相关不变性链的完整加工是必不可少的，并且在动脉粥样硬化和肺气肿的细胞外基质降解中也可能是重要的。在半胱氨酸蛋白酶中，组织蛋白酶S的活性受到IFN-γ的上调。鉴于其重要性，我们试图阐明IFN-γ增加组织蛋白酶S表达的途径。我们的数据表明，在II型肺泡上皮细胞（A549）中，组织蛋白酶S启动子包含IFN刺激反应元件（ISRE），该元件对IFN γ诱导的基因转录至关重要。从A549核提取物中提取的IFN反应因子(IRF)-2在凝胶移位试验中与ISRE寡核苷酸相关，但在IFN-γ刺激后迅速被IRF-1取代。IRF-1/ISRE复合物形成的时间进程与IRF-1蛋白和组织蛋白酶S mRNA水平的升高有关。在A549细胞中，过表达IRF-1而非IRF-2可显著增强组织蛋白酶S启动子活性。此外，IRF-1的过表达增加了293T上皮细胞内源性组织蛋白酶S mRNA的水平。最后，来自IRF-1−/−小鼠的新鲜分离的骨髓细胞不能响应IFN-γ上调组织蛋白酶S活性。因此，IRF-1是IFN-γ依赖性组织蛋白酶S激活的关键转录介质。这些数据阐明了IRF-1可能影响MHC II类加工和呈现的新途径。
Cathepsin S is a cysteine protease with potent endoproteolytic activity and a broad pH profile. Cathepsin S activity is essential for complete processing of the MHC class II-associated invariant chain within B cells and dendritic cells, and may also be important in extracellular matrix degradation in atherosclerosis and emphysema. Unique among cysteine proteases, cathepsin S activity is up-regulated by IFN-γ. Given its importance, we sought to elucidate the pathway by which IFN-γ increases cathepsin S expression. Our data demonstrate that the cathepsin S promoter contains an IFN-stimulated response element (ISRE) that is critical for IFN-γ-induced gene transcription in a cell line derived from type II alveolar epithelial (A549) cells. IFN response factor (IRF)-2 derived from A549 nuclear extracts associates with the ISRE oligonucleotide in gel shift assays, but is quickly replaced by IRF-1 following stimulation with IFN-γ. The time course of IRF-1/ISRE complex formation correlates with increased levels of IRF-1 protein and cathepsin S mRNA. Overexpression of IRF-1, but not IRF-2, markedly augments cathepsin S promoter activity in A549 cells. Furthermore, overexpression of IRF-1 increases endogenous cathepsin S mRNA levels in 293T epithelial cells. Finally, freshly isolated bone marrow cells from IRF-1−/− mice fail to up-regulate cathepsin S activity in response to IFN-γ. Thus, IRF-1 is the critical transcriptional mediator of IFN-γ-dependent cathepsin S activation. These data elucidate a new pathway by which IRF-1 may affect MHC class II processing and presentation.