Mycobacteria-induced granuloma necrosis depends on IRF-1
Mycobacteria-induced granuloma necrosis depends on IRF-1
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DOI：
10.1111/j.1582-4934.2008.00470.x
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发表时间：
2009-08-01
影响因子：
5.3
通讯作者：
Ehlers, Stefan
中科院分区：
文献类型：
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作者：
Aly, Sahar;Mages, Joerg;Ehlers, Stefan
在分枝杆菌诱导的小鼠免疫病理模型中，野生型C57BL/6 （WT）、il -18敲除（KO）和ifn - α - β受体-KO小鼠在气溶胶感染鸟分枝杆菌后出现了周围的、中央坏死性肉芽肿病变，而缺乏ifn - γ受体、stat1或IRF-1的小鼠没有出现肉芽肿坏死。通过对受感染的WT和IRF-1-KO小鼠肺部基因表达的对比分析，我们发现了一组差异调控与肉芽肿坏死密切相关的基因，其中包括组织蛋白酶K、胱抑素F和基质金属蛋白酶10。进一步以微阵列为基础比较感染WT、ifn - γ - ko和IRF-1- ko小鼠肺部的基因表达，揭示了四个不同的基因簇，它们对ifn - γ、IRF-1或两者的存在有不同的依赖性。特别是，IRF-1似乎直接参与了对分枝杆菌感染的I型免疫反应的分化。总之，IRF-1不仅仅是ifn - γ下游的转录因子，它可能是分枝杆菌诱导的免疫病理的主要调节因子。
In a mouse model of mycobacteria-induced immunopathology, wild-type C57BL/6 (WT), IL-18-knockout (KO) and IFN-alpha beta receptor-KO mice developed circumscript, centrally necrotizing granulomatous lesions in response to aerosol infection with M. avium, whereas mice deficient in the IFN-gamma receptor, STAT-1 or IRF-1 did not exhibit granuloma necrosis. Comparative, microarray-based gene expression analysis in the lungs of infected WT and IRF-1-KO mice identified a set of genes whose differential regulation was closely associated with granuloma necrosis, among them cathepsin K, cystatin F and matrix metalloprotease 10. Further microarray-based comparison of gene expression in the lungs of infected WT, IFN-gamma-KO and IRF-1-KO mice revealed four distinct clusters of genes with variable dependence on the presence of IFN-gamma, IRF-1 or both. In particular, IRF-1 appeared to be directly involved in the differentiation of a type I immune response to mycobacterial infection. In summary, IRF-1, rather than being a mere transcription factor downstream of IFN-gamma, may be a master regulator of mycobacteria-induced immunopathology.