Mycobacterium tuberculosis Induces the Production of Tumor Necrosis Factor-alpha, Interleukin-6, and CXCL8 in Pulmonary Epithelial Cells Through Reactive Oxygen Species-dependent Mitogen-activated Protein Kinase Activation.
- Author:
Hye Mi LEE
1
;
Dong Min SHIN
;
Eun Kyeong JO
Author Information
- Publication Type:Original Article
- Keywords: Mycobacterium tuberculosis; Tumor necrosis factor-alpha; Interleukin-6; CXCL8; Alveolar epithelial cells; Reactive oxygen specieeo
- MeSH: Acetylcysteine; Epithelial Cells; Interleukin-6; Interleukins; Mitogen-Activated Protein Kinases; Mycobacterium; Mycobacterium tuberculosis; NADP; Onium Compounds; Oxidoreductases; Oxygen; p38 Mitogen-Activated Protein Kinases; Phosphotransferases; Protein Kinases; Reactive Oxygen Species; Signal Transduction; Toll-Like Receptors; Tumor Necrosis Factor-alpha
- From:Journal of Bacteriology and Virology 2009;39(1):1-10
- CountryRepublic of Korea
- Language:English
- Abstract: Upon contact with airway epithelial cells, mycobacteria activate several signal transduction events that are required for induction of inflammatory cytokines/chemokines. In this study, we found that Mycobacterium tuberculosis (Mtb)induced reactive oxygen species (ROS) production is essential for the expression of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and CXC-chemokine ligand (CXCL) 8 through the activation of mitogen-activated protein kinases [MAPKs; extracellular signal-regulated kinase (ERK) 1/2 and p38 MAPK] in A549 cells representing alveolar epithelial cells. We observed that Mtb rapidly enhanced ROS production after stimulation in a toll-like receptor (TLR) 2-dependent manner. In addition, Mtb triggered ERK1/2 and p38 MAPK signaling pathways which were dependent on ROS generation in A549 cells. Moreover, Mtb stimulation significantly increased the secretion of TNF-alpha, IL-6, and CXCL8 over that in untreated controls. Pretreatment of A549 cells with the antioxidant, N-acetylcysteine and the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, diphenylene iodonium, substantially inhibited Mtb-induced production of TNF-alpha, IL-6, and CXCL8. Studies using inhibitors selective for ERK1/2 and p38 MAPK pathways showed that both pathways play an essential role in the induction of TNF-alpha, IL-6, and CXCL8 at transcriptional levels in A549 cells. Collectively, our findings indicate the critical role of TLR2-dependent ROS in the Mtb-induced inflammatory cytokine/chemokine production in alveolar epithelial cells through MAPK-dependent signaling pathways.
