title: A synthetic inhibitor of interleukin-1 beta converting enzyme prevents endotoxin-induced interleukin-1 beta production in vitro and in vivo.
abstract: A potent, reversible, tetrapeptide inhibitor of interleukin-1 beta converting enzyme (ICE), L-709,049, has been shown to suppress the in vitro production of mature IL-1 beta. We now report that this inhibitor also effectively suppresses the production of mature IL-1 beta in a murine model of endotoxic shock. Intraperitoneal administration of L-709,049 reduced the elevations of IL-1 beta in the plasma and peritoneal fluid of mice treated with LPS in a dose-related manner (ED50 = 2 +/- 0.9 mg/kg). LPS-induced elevations in IL-1 alpha and IL-6 in these mice were unaffected, indicating that the inhibitor specifically affected IL-1 beta production. Immunoblot analysis of plasma and peritoneal fluid indicated that L-709,049 suppressed the formation of mature IL-1 beta production in vivo. When mouse blood was incubated in vitro with LPS, IL-1 beta was released into the plasma. This assay was used to determine ex vivo the activity of an ICE inhibitor in the blood following its administration to mice. Blood obtained 15 minutes after ip administration of 10 mg/kg of L-709,049 to mice produced 80% less IL-1 beta than control blood, and IL-1 beta production returned to control levels in blood obtained 30 minutes after injection of this inhibitor. In addition, the capacity of the blood plasma obtained from these animals to prevent the cleavage of a synthetic substrate by ICE disappeared within 1 h of ip administration of 50 mg/kg of inhibitor.
authors.affiliation: Merck Research Laboratories, Rahway, NJ 07065, USA.
authors.forename: D S
authors.initials: DS
authors.lastname: Fletcher
authors.forename: L
authors.initials: L
authors.lastname: Agarwal
authors.forename: K T
authors.initials: KT
authors.lastname: Chapman
authors.forename: J
authors.initials: J
authors.lastname: Chin
authors.forename: L A
authors.initials: LA
authors.lastname: Egger
authors.forename: G
authors.initials: G
authors.lastname: Limjuco
authors.forename: S
authors.initials: S
authors.lastname: Luell
authors.forename: D E
authors.initials: DE
authors.lastname: MacIntyre
authors.forename: E P
authors.initials: EP
authors.lastname: Peterson
authors.forename: N A
authors.initials: NA
authors.lastname: Thornberry
mesh_terms: D000818:Animals; D001202:Ascitic Fluid / Q000276:immunology; D020170:Caspase 1; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004731:Endotoxins / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000096:biosynthesis* / Q000097:blood; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D009842:Oligopeptides / Q000493:pharmacokinetics / Q000494:pharmacology*; D011425:Propionibacterium acnes / Q000276:immunology; D012772:Shock, Septic / Q000276:immunology*
chemical_list: D015853:Cysteine Proteinase Inhibitors; D004731:Endotoxins; D007375:Interleukin-1; D008070:Lipopolysaccharides; D009842:Oligopeptides; C096429:L 709049; D003546:Cysteine Endopeptidases; D020170:Caspase 1