Signals from stressed cells and the enteric microbiota activate macrophages and dendritic cells and mediate intestinal
inflammation.
HMGB1 serves as an immunogenic stimuli causing release of inflammatory
cytokines by myeloid cells.
Ethyl pyruvate inhibits secretion of
HMGB1 and improves survival in models of
endotoxemia and
hemorrhagic shock. We reasoned that
ethyl pyruvate may be protective in
colitis, which involves similar inflammatory pathways. In IL-10(-/-) mice with established chronic
colitis,
ethyl pyruvate administration ameliorated
colitis and reduced intestinal
cytokine production. IL-10(-/-) mice demonstrated increased intestinal
HMGB1 expression and decreased expression of RAGE compared with wild-type mice. Fecal
HMGB1 levels were decreased in
ethyl pyruvate-treated mice. Furthermore,
ethyl pyruvate induced HO-1 expression in intestinal tissue. In TNBS-induced
colitis, intrarectal administration of
ethyl pyruvate resulted in amelioration of
colitis and reduced intestinal
cytokine production. In LPS-activated murine macrophages,
ethyl pyruvate decreased expression of
IL-12 p40 and NO production but did not affect
IL-10 levels.
Ethyl pyruvate did not inhibit nuclear translocation of
NF-kappaB family members but attenuated
NF-kappaB DNA binding. Additionally,
ethyl pyruvate induced HO-1
mRNA and
protein expression and HO-1 promoter activation. Moreover,
ethyl pyruvate prevented nuclear-to-cytoplasmic translocation of
HMGB1. In conclusion, the
HMGB1/RAGE pathway has pathophysiologic and diagnostic significance in experimental
colitis.
Ethyl pyruvate and other strategies to inhibit
HMGB1 release and function represent promising interventions in chronic inflammatory diseases.