International Immunology Advance Access published online on June 25, 2009
International Immunology, doi:10.1093/intimm/dxp057
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Antimicrobial cathelicidin polypeptide CAP11 suppresses the production and release of septic mediators in D-galactosamine-sensitized endotoxin shock mice
1 Department of Host Defense and Biochemical Research, Juntendo University School of Medicine, Tokyo 113-8421, Japan
2 Department of Molecular Cell Biology, Jikei University School of Medicine, Tokyo 105-8461, Japan
3 Department of Bacteriology, Juntendo University School of Medicine, Tokyo 113-8421, Japan
4 Seikagaku Biobusiness Corporation, Tokyo 101-0042, Japan
Correspondence to: I. Nagaoka; E-mail: nagaokai{at}juntendo.ac.jp
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-
, IL-1β 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.
Keywords: anandamide, HMGB1, host defense peptide, innate immunity
Transmitting editor: K. Okumura
Received 31 October 2008, accepted 22 May 2009.