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p32 is Required for Appropriate Interleukin-6 Production Upon LPS Stimulation and Protects Mice from Endotoxin Shock
Katsuhiko Sasaki1, Kazuhito Gotoh2, Sho Miake2
1Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; Medical Solution Promotion Department, Business Management Center, Medical Solution Segment, LSI Medience Corporation, 4-1, Kyudaishimmachi, Nishi-ku, Fukuoka 819-0388, Japan.
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.
Insights
Mitochondrial dysfunction in sepsis leads to excessive interleukin-6 (IL-6) production, worsening patient outcomes. This study identifies p32 as a key regulator linking mitochondrial issues to IL-6 overproduction and poor sepsis prognosis.
Area of Science:
- Cell Biology
- Immunology
- Molecular Medicine
Background:
- Sepsis is a critical condition with high mortality.
- Mitochondrial dysfunction correlates with poor sepsis outcomes.
- The link between mitochondrial dysfunction and interleukin-6 (IL-6) in sepsis is unclear.
Purpose of the Study:
- To investigate the role of p32/C1QBP/HABP1 in regulating IL-6 production during sepsis.
- To elucidate the molecular mechanisms connecting mitochondrial dysfunction to IL-6 overproduction.
Main Methods:
- Utilized p32-deficient mouse embryonic fibroblasts (MEFs) and lipopolysaccharide (LPS) stimulation.
- Employed short hairpin RNA (shRNA) to knock down activating transcription factor 4 (ATF4).
- Administered chloramphenicol to inhibit mitochondrial translation.
- Established an LPS-induced endotoxin shock mouse model with myeloid cell-specific p32 ablation.
Main Results:
- LPS induced IL-6 overproduction in p32-deficient MEFs via ATF4-dependent, NF-κB-independent pathways.
- ATF4 knockdown significantly reduced LPS-induced IL-6 in p32-deficient MEFs.
- Mitochondrial translation inhibition (chloramphenicol) led to excessive IL-6 via ATF4.
- Mice lacking p32 in myeloid cells exhibited increased lethality and IL-6 overproduction in an endotoxin shock model.
Conclusions:
- p32/C1QBP/HABP1 is identified as a crucial regulator of IL-6 production in response to LPS.
- Mitochondrial dysfunction promotes IL-6 overproduction through ATF4 pathways, contributing to poor sepsis prognosis.
- This study establishes a molecular link between mitochondrial dysfunction, IL-6 elevation, and adverse outcomes in sepsis.
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