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.
Highlights
Sepsis is a life-threatening condition that results from a harmful host response to infection
We have found that loss of mitochondrial translation due to a deficiency of p32 or the presence of inhibitors increases LPS-induced IL-6 overproduction via Activating transcription factor 4 (ATF4) activation in mouse embryonic fibroblasts (MEFs)
Our study clearly indicates that the loss of p32 enhances TLR4mediated IL-6 production via not an nuclear factor-κB (NF-κB) dependent pathway but an ATF4 dependent pathway in MEFs (Figs. 2-4)
Summary
Sepsis is a life-threatening condition that results from a harmful host response to infection. Sepsis-associated multiple organ dysfunction syndrome (MODS) is the predominant cause of mortality among seriously ill patients (Deitch, 1992). Several lines of evidence suggest that mitochondrial dysfunction is associated with poor outcomes in patients with sepsis and MODS (Brealey et al, 2002) (Brealey et al, 2004) (Duvigneau et al, 2008). Expressed at the cell surface, toll like receptor (TLR) 4 detects LPS from Gram-negative bacteria. IL-6 has been used as a prognostic marker for outcomes in septic patients, but it is still unknown whether sepsis-induced mitochondria dysfunction is associated with the production of IL-6. We have found that loss of mitochondrial translation due to a deficiency of p32 or the presence of inhibitors increases LPS-induced IL-6 overproduction via ATF4 activation in mouse embryonic fibroblasts (MEFs). Using a mice endotoxin shock model, we showed that p32 protects mice from endotoxin shock
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