Role of apoptosis-regulating signal kinase 1 in innate immune responses by Mycobacterium bovis bacillus Calmette-Guérin.
Mycobacterium bovis bacillus Calmette-Guérin (BCG) induces innate immune responses through Toll-like receptor (TLR) 2 and TLR4. We investigated the role of apoptosis-regulating signal kinase (ASK) 1 in reactive oxygen species (ROS)-mediated innate immune responses induced by BCG mycobacterial infection. In macrophages, M. bovis BCG stimulation resulted in rapid activation of mitogen-activated protein kinases (MAPKs), secretion of inflammatory cytokines, such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-6, and ROS generation in a TLR2- and TLR4-dependent manner. M. bovis BCG-induced ROS production led to robust activation of ASK1 upstream of the c-jun-N-terminal kinase and p38 MAPK, but not extracellular-regulated kinase 1/2. Blocking ASK1 activity markedly attenuated M. bovis BCG-induced TNF-alpha and IL-6 production by macrophages. Both TLR2 and TLR4 were required for optimal activation of ASK1 in response to M. bovis BCG. Furthermore, we present evidence that TNF receptor-associated factor (TRAF) 6 activities were essential for ROS-mediated ASK1 activation by M. bovis BCG. Finally, ASK1 activities were required for effective control of intracellular mycobacterial survival. Thus, the results of this study suggest a novel role of the TLR-ROS-TRAF6-ASK1 axis in the innate immune response to mycobacteria as a signaling intermediate.
Department of Microbiology, College of Medicine, Chungnam National University, Daejeon, South Korea.
Jae-Min
JM
Yuk
Dong-Min
DM
Shin
Chul-Su
CS
Yang
Ki Hye
KH
Kim
Se-Jin
SJ
An
Jaerang
J
Rho
Jeong-Kyu
JK
Park
Eun-Kyeong
EK
Jo
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D002460:Cell Line; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D048848:MAP Kinase Kinase Kinase 5 / Q000276:immunology / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D020929:Mitogen-Activated Protein Kinase Kinases / Q000276:immunology / Q000378:metabolism; D009163:Mycobacterium bovis / Q000276:immunology*; D017382:Reactive Oxygen Species / Q000276:immunology / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000276:immunology / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000276:immunology / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism; D014376:Tuberculosis / Q000201:enzymology / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
D015850:Interleukin-6; D017382:Reactive Oxygen Species; D048029:TNF Receptor-Associated Factor 6; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases