Sepsis is a state of disrupted inflammatory homeostasis that is initiated by
infection. High mobility group box 1 (
HMGB1) protein acting as a late mediator of severe vascular inflammatory conditions, such as
sepsis and
endothelial cell protein C receptor (
EPCR), is involved in vascular
inflammation.
Fisetin, an active compound from the family Fabaceae, was reported to have
antiviral, neuroprotective, and anti-inflammatory activities. Here, we determined the anti-septic effects of
fisetin on HMGB1-mediated inflammatory responses and on the shedding of
EPCR in vitro and in vivo, for the first time. First, we monitored the effects of post-treatment
fisetin on
lipopolysaccharide (LPS) and cecal
ligation and
puncture (CLP)-mediated release of
HMGB1 and HMGB1-mediated regulation of pro-inflammatory responses in human umbilical vein endothelial cells (HUVECs) and septic mice. Post-treatment
fisetin was found to suppress LPS-mediated release of
HMGB1 and HMGB1-mediated cytoskeletal rearrangements.
Fisetin also inhibited HMGB1-mediated hyperpermeability and leukocyte migration in septic mice.
Fisetin induced potent inhibition of
phorbol-12-myristate 13-acetate (PMA) and CLP-induced
EPCR.
Fisetin also inhibited the expression and activity of
tumor necrosis factor-α converting
enzyme, induced by PMA in endothelial cells. In addition,
fisetin inhibited the production of
tumor necrosis factor-α and the activation of AKT, nuclear factor-κB, and extracellular regulated
kinases 1/2 by
HMGB1 in HUVECs.
Fisetin also down-regulated CLP-induced release of
HMGB1, production of
interleukin 1β, and reduced septic mortality. Collectively, these results suggest that
fisetin may be a candidate therapeutic agent for the treatment of vascular inflammatory diseases via inhibition of the
HMGB1 signaling pathway.