Modulation of inflammatory response in sepsis by proteasome inhibition.
The Ubiquitin-proteasome system has recently been shown to be involved in the regulation of cytokine expression. We tested the hypothesis of whether the in vivo administration of proteasome inhibitor MG-132 can modulate cytokine response and mortality in sepsis. Sepsis was induced in mice by caecal ligation and puncture (CLP). Animals were divided into four groups: control, CLP, CLP and 1 microg MG-132/g of b.w. intraperitoneally, and CLP and 10 microg MG-132/g of b.w. Plasma levels of interleukin (IL)-1, tumour necrosis factor-alpha (TNF-alpha, IL-6 and IL-10 were determined by ELISA 6 h after the induction of sepsis. CLP induced significant increase in plasma levels of all measured cytokines. MG-132 treatment resulted in lower increase in IL-1, TNF-alpha and IL-10 levels. IL-6 was not significantly affected. A mortality study revealed prolonged survival in MG-132 treated mice. We conclude that MG-132 treatment decreases inflammatory response and prolongs survival in the CLP model of sepsis.
Safránek
Roman
R
Department of Surgery, School of Medicine, Kurume University, Kurume, Japan. SafranekR@lfhk.cuni.cz
Ishibashi
Nobuya
N
Oka
Youske
Y
Ozasa
Hiroyuki
H
Shirouzu
Kazuo
K
Holecek
Milan
M
D000818:Animals; D015853:Cysteine Proteinase Inhibitors / Q000627:therapeutic use*; D016207:Cytokines / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005260:Female; D018836:Inflammation Mediators / Q000097:blood*; D007976:Leupeptins / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D061988:Proteasome Inhibitors; D018805:Sepsis / Q000097:blood / Q000188:drug therapy*; D016019:Survival Analysis
D015853:Cysteine Proteinase Inhibitors; D016207:Cytokines; D018836:Inflammation Mediators; D007976:Leupeptins; D061988:Proteasome Inhibitors; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde