title: Interleukin-1 beta converting enzyme inhibition blocks progression of type II collagen-induced arthritis in mice.
abstract: To IL-1 beta is a principal mediator in the pathogenesis of inflammatory disease. The IL-1 beta-converting enzyme (ICE), a novel cysteine protease, is required for processing of the 31 kDa IL-1 beta precursor to generate the 17 kDa proinflammatory mature form. We investigated the effect of two irreversible peptidyl ICE inhibitors, VE-13,045 and VE-16,084, on IL-1 production in vitro and in vivo in acute and chronic inflammatory disease models. In vitro, VE-13,045 and VE-16084 inhibited IL-1 beta secretion by LPS-stimulated human adherent mononuclear cells (IC50's of 0.4 microM and 2.0 microM, respectively) and murine splenic monocytes (IC50's of 10 microM and 1.3 microM, respectively). Both VE-13,045 and VE-16,084 also inhibited LPS stimulated IL-1 alpha secretion, although with reduced potency. In vivo, a single intraperitoneal dose of VE-13,045 (50 mg/kg) administered to mice 60 to 75 minutes after a 40 mg/kg LPS challenge significantly reduced IL-1 beta serum levels by 50 to 70%. In the DBA/1J mouse model of Type II collagen-induced arthritis, prophylactic treatment with VE-13,045 (50 and 100 mg/kg/day) significantly delayed the onset of inflammation, with a 60% overall reduction in disease severity. VE-13,045 was more effective than either indomethacin (2 mg/kg/day) or methyl prednisolone (10 mg/kg/day). VE-13,045 was also effective in reducing inflammation and progression of arthritis when administered to mice with established disease. Histological analysis of wrist joints showed a reduction in synovial membrane damage, inflammatory cell infiltration and fibrosis, and cartilage erosion in VE-13,045-treated animals. This is the first demonstration of efficacy for an ICE inhibitor in a chronic disease model and suggests that ICE is an important target for design of anti-inflammatory or disease modifying drugs.
authors.affiliation: Vertex Pharmaceuticals Incorporated, Cambridge, MA 01239, USA.
authors.forename: G
authors.initials: G
authors.lastname: Ku
authors.forename: T
authors.initials: T
authors.lastname: Faust
authors.forename: L L
authors.initials: LL
authors.lastname: Lauffer
authors.forename: D J
authors.initials: DJ
authors.lastname: Livingston
authors.forename: M W
authors.initials: MW
authors.lastname: Harding
mesh_terms: D000818:Animals; D001168:Arthritis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D002478:Cells, Cultured; D003094:Collagen / Q000633:toxicity*; D015853:Cysteine Proteinase Inhibitors / Q000008:administration & dosage*; D004195:Disease Models, Animal; D006801:Humans; D007375:Interleukin-1 / Q000097:blood*; D051379:Mice; D009842:Oligopeptides / Q000008:administration & dosage*
chemical_list: D015853:Cysteine Proteinase Inhibitors; D007375:Interleukin-1; D009842:Oligopeptides; C103483:VE 13045; C103484:VE 16084; D003094:Collagen