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: G Ku, T Faust, L L Lauffer, D J Livingston, M W Harding
• Journal: Cytokine (Cytokine) Vol. 8 Issue 5 Pg. 377-86 (May 1996) ISSN: 1043-4666 [Print] England
• PMID: 8726666 (Publication Type: Journal Article)

Chemical References

• Cysteine Proteinase Inhibitors
• Interleukin-1
• Oligopeptides
• VE 13045
• VE 16084
• Collagen

Topics

• Animals
• Arthritis (chemically induced, drug therapy, metabolism)
• Cells, Cultured
• Collagen (toxicity)
• Cysteine Proteinase Inhibitors (administration & dosage)
• Disease Models, Animal
• Humans
• Interleukin-1 (blood)
• Mice
• Oligopeptides (administration & dosage)