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Activated protein C inhibits high mobility group box 1 signaling in endothelial cells

Jong-Sup Bae1, Alireza R Rezaie

  • 1College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Republic of Korea. baejs@knu.ac.kr

Blood
|August 19, 2011
PubMed

Insights

Activated protein C (APC) inhibits high-mobility group box 1 (HMGB1) signaling in severe sepsis. This mechanism, involving EPCR and PAR-1, offers potential therapeutic strategies by reducing inflammation and cell adhesion.

Area of Science:

  • Biochemistry
  • Immunology
  • Critical Care Medicine

Background:

  • High-mobility group box 1 (HMGB1) protein is implicated in severe sepsis pathogenesis.
  • Activated protein C (APC) is an FDA-approved treatment for severe sepsis, but its impact on HMGB1 signaling is unknown.

Purpose of the Study:

  • To investigate the effect of APC on HMGB1 release and signaling in lipopolysaccharide-activated human umbilical vein endothelial cells (HUVECs).
  • To determine the role of HMGB1 receptors (TLR2, TLR4, AGE receptor) in APC's protective mechanisms.

Main Methods:

  • Monitoring APC's effect on lipopolysaccharide-induced HMGB1 release in HUVECs.
  • Assessing APC's impact on THP-1 cell adhesion to HMGB1-activated HUVECs.
  • Evaluating APC's modulation of HMGB1 receptor expression and signaling pathways (EPCR, PAR-1).

Main Results:

  • APC significantly inhibited HMGB1 release and THP-1 cell adhesion.
  • APC down-regulated the expression of HMGB1 receptors (TLR2, TLR4, AGE receptor) on endothelial cells.
  • APC's protective effects were mediated via EPCR and PAR-1, with a thrombin derivative showing enhanced efficacy.

Conclusions:

  • APC exerts protective effects in severe sepsis partly by inhibiting HMGB1 signaling through EPCR and PAR-1.
  • A chimeric thrombin mutant targeting these pathways demonstrates potential therapeutic value for severe sepsis.

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