Endotoxin shock is a severe systemic inflammatory response that is caused by the augmented production and release of septic mediators. Among them, inflammatory
cytokines such as
tumor necrosis factor-alpha, IL-1beta and
IL-6 play a pivotal role. In addition,
anandamide, an endogenous
cannabinoid and high-mobility group box-1 (
HMGB1), a non-
histone chromosomal
protein has recently been recognized as members of septic mediators. We previously reported that cationic antibacterial
polypeptide of 11-kDa (CAP11), an antimicrobial
cathelicidin peptide (originally isolated from guinea pig neutrophils), potently neutralizes the
biological activity of LPS and protects mice from lethal
endotoxin shock. In this study, to clarify the protective mechanism of CAP11 against
endotoxin shock, we evaluated the effects of CAP11 on the production and release of septic mediators in vitro and in vivo using a murine macrophage cell line RAW264.7 and a D-
galactosamine-sensitized murine
endotoxin shock model. LPS stimulation induced the production of inflammatory
cytokines and
anandamide and release of
HMGB1 from RAW264.7 cells. Importantly, CAP11 suppressed the LPS-induced production and release of these mediators by RAW264.7 cells. Moreover, LPS administration enhanced the serum levels of
HMGB1,
anandamide and inflammatory
cytokines in the
endotoxin shock model. Of note, CAP11 suppressed the LPS-induced increase of these mediators in sera, and LPS binding to CD14-positive cells (peritoneal macrophages), accompanied with the increase of survival rates. Together these observations suggest that the protective action of CAP11 on
endotoxin shock may be explained by its suppressive effect on the production and release of septic mediators by CD14-positive cells possibly via the inhibition of LPS binding to the targets.