Abstract
Sepsis is a major clinical challenge with unacceptably high mortality. The signal transducers and activators of transcription (STAT) family of transcription factors is known to activate critical mediators of cytokine responses, and, among this family, STAT3 is implicated to be a key transcription factor in both immunity and inflammatory pathways. We investigated whether in vivo introduction of synthetic double-stranded STAT3 decoy oligodeoxynucleotides (ODNs) can provide benefits for reducing organ injury and mortality in mice with cecal ligation and puncture (CLP)-induced polymicrobial sepsis. We found that STAT3 was rapidly activated in major end-organ tissues following CLP, which was accompanied by activation of the upstream kinase JAK2. Transfection of STAT3 decoy ODNs downregulated pro-inflammatory cytokine/chemokine overproduction in CLP mice. Moreover, STAT3 decoy ODN transfection significantly reduced the increases in tissue mRNAs and proteins of high mobility group box 1 (HMGB1) and strongly suppressed the excessive elevation in serum HMGB1 levels in CLP mice. Finally, STAT3 decoy ODN administration minimized the development of sepsis-driven major end-organ injury and led to a significant survival advantage in mice after CLP. Our results suggest a critical role of STAT3 in the sepsis pathophysiology and the potential usefulness of STAT3 decoy ODNs for sepsis gene therapy.
Highlights
Sepsis is a major clinical challenge with unacceptably high mortality
We have demonstrated that in vivo administration of decoy ODNs with a circular dumbbell structure binding to another transcription factor activator protein-1 (AP-1), which is activated during sepsis in a different time-dependent manner from Nuclear factor-κB (NF-κB), can lead to a significant survival advantage in the late phase of sepsis in mice rendered septic by cecal ligation and puncture (CLP) without effect on early m ortality[18]
STAT3 phosphorylation profoundly increased in all tissues after CLP in a time-dependent manner, the time course of increases in STAT3 phosphorylation was somewhat different among tissues
Summary
Sepsis is a major clinical challenge with unacceptably high mortality. The signal transducers and activators of transcription (STAT) family of transcription factors is known to activate critical mediators of cytokine responses, and, among this family, STAT3 is implicated to be a key transcription factor in both immunity and inflammatory pathways. We have demonstrated that in vivo administration of decoy ODNs with a circular dumbbell structure binding to another transcription factor activator protein-1 (AP-1), which is activated during sepsis in a different time-dependent manner from NF-κB, can lead to a significant survival advantage in the late phase of sepsis in mice rendered septic by CLP without effect on early m ortality[18] This suggests that AP-1 may play a pivotal role as a transcription factor in the late phase of sepsis[17,18]. Our studies demonstrate that inhibiting the STAT3 pathway can downregulate pro-inflammatory cytokines, reduce tissue inflammation, minimize the development of key organ failure, and improve survival in septic mice, suggesting that STAT3 may be developed as an attractive and potential therapeutic target for treatment of sepsis
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