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

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)161-172
Number of pages12
JournalEBioMedicine
Volume20
DOIs
Publication statusPublished - Jun 2017

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint Dive into the research topics of 'p32 is Required for Appropriate Interleukin-6 Production Upon LPS Stimulation and Protects Mice from Endotoxin Shock'. Together they form a unique fingerprint.

Cite this