title: Mycobacterial HBHA induces endoplasmic reticulum stress-mediated apoptosis through the generation of reactive oxygen species and cytosolic Ca2+ in murine macrophage RAW 264.7 cells.
abstract: Mycobacterial heparin-binding haemagglutinin antigen (HBHA) is a virulence factor that induces apoptosis of macrophages. Endoplasmic reticulum (ER) stress-mediated apoptosis is an important regulatory response that can be utilised to study the pathogenesis of tuberculosis. In the present study, HBHA stimulation induced ER stress sensor molecules in a caspase-dependent manner. Pre-treatment of RAW 264.7 cells with an IκB kinase 2 inhibitor reduced not only C/EBP homology protein expression but also IL-6 and monocyte chemotactic protein-1 (MCP-1) production. BAPTA-AM reduced both ER stress responses and caspase activation and strongly suppressed HBHA-induced IL-6 and MCP-1 production in RAW 264.7 cells. Enhanced reactive oxygen species (ROS) production and elevated cytosolic [Ca(2+)]i levels were essential for HBHA-induced ER stress responses. Collectively, our data suggest that HBHA induces cytosolic [Ca(2+)]i, which influences the generation of ROS associated with the production of proinflammatory cytokines. These concerted and complex cellular responses induce ER stress-associated apoptosis during HBHA stimulation in macrophages. These results indicate that the ER stress pathway has an important role in the HBHA-induced apoptosis during mycobacterial infection.
authors: 1] Department of Microbiology, College of Medicine, Chungnam National University, Daejeon, South Korea [2] Infection Signaling Network Research Center, College of Medicine, Chungnam National University, Daejeon, South Korea.
authors: J-A
authors: JA
authors: Choi
authors: 1] Department of Microbiology, College of Medicine, Chungnam National University, Daejeon, South Korea [2] Infection Signaling Network Research Center, College of Medicine, Chungnam National University, Daejeon, South Korea.
authors: Y-J
authors: YJ
authors: Lim
authors: 1] Department of Microbiology, College of Medicine, Chungnam National University, Daejeon, South Korea [2] Infection Signaling Network Research Center, College of Medicine, Chungnam National University, Daejeon, South Korea.
authors: S-N
authors: SN
authors: Cho
authors: 1] Department of Microbiology, College of Medicine, Chungnam National University, Daejeon, South Korea [2] Infection Signaling Network Research Center, College of Medicine, Chungnam National University, Daejeon, South Korea.
authors: J-H
authors: JH
authors: Lee
authors: Department of Physiology, College of Medicine, Chungnam National University, Daejeon, South Korea.
authors: J A
authors: JA
authors: Jeong
authors: Department of Physiology, College of Medicine, Konyang University, Daejeon, South Korea.
authors: E J
authors: EJ
authors: Kim
authors: 1] Infection Signaling Network Research Center, College of Medicine, Chungnam National University, Daejeon, South Korea [2] Department of Physiology, College of Medicine, Chungnam National University, Daejeon, South Korea [3] Research Institute for Medical Sciences, College of Medicine, Chungnam National University, Daejeon, South Korea.
authors: J B
authors: JB
authors: Park
authors: Department of Physiology, College of Medicine, Konyang University, Daejeon, South Korea.
authors: S H
authors: SH
authors: Kim
authors: Department of Physiology, College of Medicine, Konyang University, Daejeon, South Korea.
authors: H S
authors: HS
authors: Park
authors: 1] Department of Microbiology, College of Medicine, Chungnam National University, Daejeon, South Korea [2] Infection Signaling Network Research Center, College of Medicine, Chungnam National University, Daejeon, South Korea [3] Research Institute for Medical Sciences, College of Medicine, Chungnam National University, Daejeon, South Korea.
authors: H-J
authors: HJ
authors: Kim
authors: 1] Department of Microbiology, College of Medicine, Chungnam National University, Daejeon, South Korea [2] Infection Signaling Network Research Center, College of Medicine, Chungnam National University, Daejeon, South Korea [3] Research Institute for Medical Sciences, College of Medicine, Chungnam National University, Daejeon, South Korea.
authors: C-H
authors: CH
authors: Song
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D003600:Cytosol / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D037102:Lectins / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D037102:Lectins; D017382:Reactive Oxygen Species; C104578:heparin-binding hemagglutinin; D002118:Calcium