PMID- 25544271 OWN - NLM STAT- MEDLINE DCOM- 20151116 LR - 20220321 IS - 1573-675X (Electronic) IS - 1360-8185 (Linking) VI - 20 IP - 3 DP - 2015 Mar TI - Mycobacterium tuberculosis 38-kDa antigen induces endoplasmic reticulum stress-mediated apoptosis via toll-like receptor 2/4. PG - 358-70 LID - 10.1007/s10495-014-1080-2 [doi] AB - Endoplasmic reticulum (ER) stress responses play critical roles in the pathogenesis of tuberculosis. To investigate the regulatory role of the ER stress response in 38-kDa antigen-induced apoptosis, we examined the relationship between the ER stress response and apoptosis in bone marrow-derived macrophages (BMDMs) stimulated with Mycobacterium tuberculosis antigen (38-kDa Ag). The expression of ER molecular chaperones, including C/EBP homologous protein (CHOP), glucose-regulated protein (Bip) and phosphorylated alpha subunit of eukaryotic initiation factor 2, was induced in BMDMs stimulated with the 38-kDa Ag. Interestingly, 38-kDa Ag-stimulation induced apoptosis via activation of caspase-12, -9 and -3. However, 38-kDa Ag-induced apoptosis was significantly reduced in TLR2- and TLR4-deficient macrophages. Because toll-like receptors (TLRs) initiate the activation of mitogen-activated protein kinase (MAPK) signaling cascades, we evaluated the effect of MAPK activation on ER stress. The 38-kDa Ag activated Jun N-terminal kinase, extracellular signal-regulated kinase and p38 phosphorylation. MAPK signaling induced the secretion of proinflammatory cytokines such as MCP-1, TNF-alpha and IL-6. The 38-kDa Ag-induced MCP-1 was especially associated with the induction of MCP-1-induced protein (MCPIP), which increased the generation of reactive oxygen species (ROS) and ER stress. To investigate the role of MCPIP in ROS-induced ER stress by 38-kDa Ag stimulation, we transfected MCPIP siRNA into RAW264.7 cells before 38-kDa Ag stimulation, and measured the generation of ROS and expression of ER molecular chaperones. ROS production and CHOP expression were decreased by the silencing of MCPIP induction. Our results demonstrate that the expression of MCPIP by 38-kDa Ag stimulation is increased through a TLR-MAPK-dependent signaling pathway, and leads to ER stress-induced apoptosis. In conclusion, MCPIP is important for host defense mechanisms in mycobacterial pathogenesis. FAU - Lim, Yun-Ji AU - Lim YJ AD - Department of Microbiology, College of Medicine, Chungnam National University, 266 Munhwa-ro, Jung-gu, Daejeon, 301-747, South Korea. FAU - Choi, Ji-Ae AU - Choi JA FAU - Lee, Jeong-Hwan AU - Lee JH FAU - Choi, Chul Hee AU - Choi CH FAU - Kim, Hwa-Jung AU - Kim HJ FAU - Song, Chang-Hwa AU - Song CH LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - Netherlands TA - Apoptosis JT - Apoptosis : an international journal on programmed cell death JID - 9712129 RN - 0 (Antigens, Bacterial) RN - 0 (Cytokines) RN - 0 (Ddit3 protein, mouse) RN - 0 (Endoplasmic Reticulum Chaperone BiP) RN - 0 (Eukaryotic Initiation Factor-2) RN - 0 (Heat-Shock Proteins) RN - 0 (RNA, Small Interfering) RN - 0 (Reactive Oxygen Species) RN - 0 (Tlr2 protein, mouse) RN - 0 (Tlr4 protein, mouse) RN - 0 (Toll-Like Receptor 2) RN - 0 (Toll-Like Receptor 4) RN - 144058-44-6 (Mycobacterium tuberculosis antigens) RN - 147336-12-7 (Transcription Factor CHOP) RN - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases) RN - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases) RN - EC 3.1.- (Ribonucleases) RN - EC 3.1.- (Zc3h12a protein, mouse) RN - EC 3.4.22.- (Caspases) SB - IM MH - Animals MH - Antigens, Bacterial/*pharmacology MH - Apoptosis/*drug effects MH - Bone Marrow Cells/drug effects/metabolism/pathology MH - Caspases/genetics/metabolism MH - Cytokines/genetics/metabolism MH - Endoplasmic Reticulum Chaperone BiP MH - Endoplasmic Reticulum Stress/*drug effects/genetics MH - Eukaryotic Initiation Factor-2/genetics/metabolism MH - Gene Expression Regulation MH - Heat-Shock Proteins/genetics/metabolism MH - JNK Mitogen-Activated Protein Kinases/genetics/metabolism MH - Macrophages/*drug effects/metabolism/pathology MH - Mice MH - Mice, Inbred C57BL MH - Mycobacterium tuberculosis/chemistry MH - Primary Cell Culture MH - RNA, Small Interfering/genetics/metabolism MH - Reactive Oxygen Species/metabolism MH - Ribonucleases/antagonists & inhibitors/genetics/metabolism MH - Signal Transduction MH - Toll-Like Receptor 2/*genetics/metabolism MH - Toll-Like Receptor 4/*genetics/metabolism MH - Transcription Factor CHOP/genetics/metabolism MH - p38 Mitogen-Activated Protein Kinases/genetics/metabolism EDAT- 2014/12/30 06:00 MHDA- 2015/11/17 06:00 CRDT- 2014/12/30 06:00 PHST- 2014/12/30 06:00 [entrez] PHST- 2014/12/30 06:00 [pubmed] PHST- 2015/11/17 06:00 [medline] AID - 10.1007/s10495-014-1080-2 [doi] PST - ppublish SO - Apoptosis. 2015 Mar;20(3):358-70. doi: 10.1007/s10495-014-1080-2.