TY - JOUR
T1 - p32 is Required for Appropriate Interleukin-6 Production Upon LPS Stimulation and Protects Mice from Endotoxin Shock
AU - Sasaki, Katsuhiko
AU - Gotoh, Kazuhito
AU - Miake, Sho
AU - Setoyama, Daiki
AU - Yagi, Mikako
AU - Igami, Ko
AU - Uchiumi, Takeshi
AU - Kang, Donchon
N1 - Funding Information:
This study was supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS; grant numbers #16K19196, #26860512 #25893162 to K.G., #15H04764, #24590387 to T.U., and #17H01550, #25253041 to D.K.). This work was partly supported by research funds from LSI Medience Corporation.
Publisher Copyright:
© 2017 The Authors
PY - 2017/6
Y1 - 2017/6
N2 - Sepsis is a major cause of morbidity and mortality in seriously ill patients and mitochondrial dysfunction is associated with poor outcomes in septic patients. Although interleukin-6 (IL-6) is a good prognostic marker for sepsis, the relationship between mitochondrial dysfunction and IL-6 remains poorly understood. We identified p32/C1QBP/HABP1 as a regulator of IL-6 production in response to lipopolysaccharide (LPS). LPS induced IL-6 overproduction in p32 deficient mouse embryonic fibroblasts (MEFs) through NF-κB independent but activating transcription factor (ATF) 4 dependent pathways. Short hairpin RNA-based knockdown of ATF4 in p32 deficient MEFs markedly inhibited LPS-induced IL-6 production. Furthermore, MEFs treated with chloramphenicol, an inhibitor of mitochondrial translation, produced excessive IL-6 via ATF4 pathways. Using a LPS-induced endotoxin shock model, mice with p32 ablation in myeloid cells showed increased lethality and overproduction of IL-6. Thus, this study provides a molecular link how mitochondrial dysfunction leads to IL-6 overproduction and poor prognosis of sepsis.
AB - Sepsis is a major cause of morbidity and mortality in seriously ill patients and mitochondrial dysfunction is associated with poor outcomes in septic patients. Although interleukin-6 (IL-6) is a good prognostic marker for sepsis, the relationship between mitochondrial dysfunction and IL-6 remains poorly understood. We identified p32/C1QBP/HABP1 as a regulator of IL-6 production in response to lipopolysaccharide (LPS). LPS induced IL-6 overproduction in p32 deficient mouse embryonic fibroblasts (MEFs) through NF-κB independent but activating transcription factor (ATF) 4 dependent pathways. Short hairpin RNA-based knockdown of ATF4 in p32 deficient MEFs markedly inhibited LPS-induced IL-6 production. Furthermore, MEFs treated with chloramphenicol, an inhibitor of mitochondrial translation, produced excessive IL-6 via ATF4 pathways. Using a LPS-induced endotoxin shock model, mice with p32 ablation in myeloid cells showed increased lethality and overproduction of IL-6. Thus, this study provides a molecular link how mitochondrial dysfunction leads to IL-6 overproduction and poor prognosis of sepsis.
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U2 - 10.1016/j.ebiom.2017.05.018
DO - 10.1016/j.ebiom.2017.05.018
M3 - Article
C2 - 28549777
AN - SCOPUS:85019558939
VL - 20
SP - 161
EP - 172
JO - EBioMedicine
JF - EBioMedicine
SN - 2352-3964
ER -