title: The involvement of NADPH oxidase-mediated ROS in cytokine secretion from macrophages induced by Mycobacterium tuberculosis ESAT-6.
abstract: The 6-kDa early secretory antigenic target (ESAT-6) of Mycobacterium tuberculosis is strongly correlated with subversion of innate immune responses against invading mycobacteria. To understand the role of ESAT-6 in macrophage response against M. tuberculosis, the effects of ESAT-6 on macrophage generation of reactive oxygen species (ROS) and production of cytokines were studied. ESAT-6-induced macrophage secretion of monocyte chemoattractant protein-1 and TNF-α was found in a time- and dose-dependent manner. Signaling inhibition experiments indicate that NF-κB activation mediated by p38/JNK mitogen-activated protein kinase (MAPK) was involved in ESAT-6-triggered cytokine production. Moreover, TLR2 was engaged in ESAT-6-stimulated macrophage activation via rapidly induced ROS production and regulated activation of JNK/p38 MAPKs and NF-κB. More importantly, NADPH oxidase-mediated ROS generation is required during this process. Our study has identified a novel signal transduction pathway involving NADPH-ROS-JNK/p38-NF-κB in ESAT-6-induced cytokine production from macrophages. These findings provide an important evidence to understand the pathogenesis of M. tuberculosis infection in the modulation of the immune response.
authors.affiliation: Department of Immunology, Tongji University School of Medicine, Medical Research Building, Rm F509, 1239 Siping Road, Shanghai, 200092, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Liu
authors.forename: Yuan
authors.initials: Y
authors.lastname: Peng
authors.forename: Yanlin
authors.initials: Y
authors.lastname: Yin
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Zhou
authors.forename: Wanding
authors.initials: W
authors.lastname: Zhou
authors.forename: Yalei
authors.initials: Y
authors.lastname: Dai
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology*; D001426:Bacterial Proteins / Q000276:immunology*; D002460:Cell Line; D018932:Chemokine CCL2 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D051550:I-kappa B Kinase / Q000276:immunology; D048031:JNK Mitogen-Activated Protein Kinases / Q000276:immunology; D020935:MAP Kinase Signaling System; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D019255:NADPH Oxidases / Q000235:genetics*; D034622:RNA Interference; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000276:immunology; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000276:immunology
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D016207:Cytokines; C093276:ESAT-6 protein, Mycobacterium tuberculosis; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C498144:Rela protein, mouse; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D019255:NADPH Oxidases; D051550:I-kappa B Kinase; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases