p32 is Required for Appropriate Interleukin-6 Production Upon LPS Stimulation and Protects Mice from Endotoxin Shock

Katsuhiko Sasaki, Kazuhito Gotoh, Sho Miake, Daiki Setoyama, Mikako Yagi, Ko Igami, Takeshi Uchiumi, Donchon Kang

研究成果: ジャーナルへの寄稿記事

4 引用 (Scopus)

抄録

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.

元の言語英語
ページ(範囲)161-172
ページ数12
ジャーナルEBioMedicine
20
DOI
出版物ステータス出版済み - 6 2017

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Endotoxins
Lipopolysaccharides
Shock
Interleukin-6
Fibroblasts
Sepsis
Activating Transcription Factor 4
Myeloid Cells
Chloramphenicol
Ablation
Small Interfering RNA
Morbidity
Mortality

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

これを引用

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title = "p32 is Required for Appropriate Interleukin-6 Production Upon LPS Stimulation and Protects Mice from Endotoxin Shock",
abstract = "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.",
author = "Katsuhiko Sasaki and Kazuhito Gotoh and Sho Miake and Daiki Setoyama and Mikako Yagi and Ko Igami and Takeshi Uchiumi and Donchon Kang",
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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

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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