Abstract |
The proinflammatory cytokine IL-1 beta is synthesized by activated monocytes and macrophages as a 31-kDa, biologically inactive precursor that is proteolytically processed to the biologically active 17-kDa mature molecule by the IL-1 beta converting enzyme ( ICE). WIN 67694, Z-Val- Ala-Asp-CH2O(CO)[2,6-(CI2)]Ph, is a potent, selective inhibitor of human ICE. In activated murine peritoneal macrophages, WIN 67694 inhibited the release of mature IL-1 beta with an IC50 of 1.8 microM without any effect on the release of IL-1 alpha, IL-6, or TNF-alpha. The effect was specific to mature IL-1 beta release; the ICE inhibitor did not effect IL-1 beta RNA levels or precursor protein synthesis. In vivo, WIN 67694 was also able to inhibit selectively the release of IL-1 beta in a dose-dependent manner in a subcutaneous tissue chamber implant model of inflammation. IL-1 beta levels in tissue chamber fluid were inhibited 35 and 55% at 10 and 100 mg/kg, respectively. IL-1 alpha, IL-6, and TNF-alpha levels were not affected. The ability to selectively inhibit mature IL-1 beta release in vivo with ICE inhibitors will allow for detailed studies of the role of IL-1 beta and ICE in inflammatory diseases.
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Authors | B E Miller, P A Krasney, D M Gauvin, K B Holbrook, D J Koonz, R V Abruzzese, R E Miller, K A Pagani, R E Dolle, M A Ator |
Journal | Journal of immunology (Baltimore, Md. : 1950)
(J Immunol)
Vol. 154
Issue 3
Pg. 1331-8
(Feb 01 1995)
ISSN: 0022-1767 [Print] United States |
PMID | 7822802
(Publication Type: Journal Article)
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Chemical References |
- Cysteine Proteinase Inhibitors
- Interleukin-1
- Oligopeptides
- RNA, Messenger
- WIN 67694
- Cysteine Endopeptidases
- Caspase 1
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Topics |
- Amino Acid Sequence
- Animals
- Caspase 1
- Cysteine Endopeptidases
(drug effects)
- Cysteine Proteinase Inhibitors
(pharmacology)
- Enzyme-Linked Immunosorbent Assay
- Female
- In Vitro Techniques
- Inflammation
(immunology)
- Interleukin-1
(biosynthesis)
- Macrophages, Peritoneal
(drug effects, immunology)
- Mice
- Mice, Inbred BALB C
- Molecular Sequence Data
- Oligopeptides
(pharmacology)
- RNA, Messenger
(biosynthesis)
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