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)‐α 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‐α 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.