Early Secreted Antigenic Target of 6 kDa (ESAT-6) Protein of Mycobacterium tuberculosis Induces Interleukin-8 (IL-8) Expression in Lung Epithelial Cells via Protein Kinase Signaling and Reactive Oxygen Species
Early Secreted Antigenic Target of 6 kDa (ESAT-6) Protein of Mycobacterium tuberculosis Induces Interleukin-8 (IL-8) Expression in Lung Epithelial Cells via Protein Kinase Signaling and Reactive Oxygen Species
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DOI：
10.1074/jbc.m112.448217
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发表时间：
2013-08-30
影响因子：
4.8
通讯作者：
Samten, Buka
中科院分区：
文献类型：
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作者：
Boggaram, Vijay;Gottipati, Koteswara R.;Samten, Buka
结核分枝杆菌早期分泌的6 kDa抗原靶点（ESAT-6）对结核分枝杆菌的毒力和致病性至关重要。结核IL-8是中性粒细胞和T淋巴细胞的主要趋化因子，在肺损伤的发生发展中起重要作用。为了进一步了解ESAT-6在肺结核发展相关的肺病理学中的作用，我们研究了ESAT-6对肺上皮细胞中IL-8表达的调节作用。ESAT-6通过增加IL-8基因转录和mRNA稳定性诱导IL-8表达。ESAT-6对IL-8启动子活性的诱导依赖于核因子-κ B（NF-κ B）和激活蛋白-1（AP-1）的结合，并且对PKC和ERK以及p38 MAPK通路的药理学抑制敏感。ESAT-6激活ERK和p38 MAPK磷酸化，并迅速诱导活性氧（ROS）的产生。二甲基硫脲而不是甘露醇抑制ESAT-6诱导的IL-8，进一步支持ROS参与诱导IL-8表达。小鼠暴露于ESAT-6诱导局部炎性细胞聚集体形成，具有早期肉芽肿的特征，伴随细支气管和肺泡II型上皮细胞和肺泡巨噬细胞中角质形成细胞趋化因子CXCL 1染色增加。我们的研究已经确定了ESAT-6诱导肺上皮细胞中IL-8表达的信号转导途径，包括ROS、PKC、ERK和p38 MAPK以及NF-κ B和AP-1。这对了解肺结核的天然免疫反应和肺结核损伤的发病机制具有重要意义。
Early secreted antigenic target of 6 kDa (ESAT-6) of Mycobacterium tuberculosis is critical for the virulence and pathogenicity of M. tuberculosis. IL-8, a major chemotactic cytokine for neutrophils and T lymphocytes, plays important roles in the development of lung injury. To further understand the role of ESAT-6 in lung pathology associated with tuberculosis development, we studied the effects of ESAT-6 on the regulation of IL-8 expression in lung epithelial cells. ESAT-6 induced IL-8 expression by increasing IL-8 gene transcription and mRNA stability. ESAT-6 induction of IL-8 promoter activity was dependent on nuclear factor-kappa B (NF-kappa B) and activator protein-1 (AP-1) binding and sensitive to pharmacological inhibition of PKC and ERK and p38 MAPK pathways. ESAT-6 activated ERK and p38 MAPK phosphorylation and rapidly induced reactive oxygen species (ROS) production. Dimethylthiourea but not mannitol inhibited IL-8 induction by ESAT-6, further supporting the involvement of ROS in the induction of IL-8 expression. Exposure of mice to ESAT-6 induced localized inflammatory cell aggregate formation with characteristics of early granuloma concomitant with increased keratinocyte chemoattractant CXCL1 staining in bronchiolar and alveolar type II epithelial cells and alveolar macrophages. Our studies have identified a signal transduction pathway involving ROS, PKC, ERK, and p38 MAPKs and NF-kappa B and AP-1 in the ESAT-6 induction of IL-8 expression in lung epithelial cells. This has important implications for the understanding of lung innate immune responses to tuberculosis and the pathogenesis of lung injury in tuberculosis.