Inhibition of mature IL-1 beta production in murine macrophages and a murine model of inflammation by WIN 67694, an inhibitor of IL-1 beta converting enzyme.
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.
Miller
B E
BE
Department of Inflammation Pharmacology, Sterling Winthrop Pharmaceuticals Research Division, Collegeville, PA 19426.
Krasney
P A
PA
Gauvin
D M
DM
Holbrook
K B
KB
Koonz
D J
DJ
Abruzzese
R V
RV
Miller
R E
RE
Pagani
K A
KA
Dolle
R E
RE
Ator
M A
MA
D000595:Amino Acid Sequence; D000818:Animals; D020170:Caspase 1; D003546:Cysteine Endopeptidases / Q000187:drug effects*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D066298:In Vitro Techniques; D007249:Inflammation / Q000276:immunology*; D007375:Interleukin-1 / Q000096:biosynthesis*; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis
D015853:Cysteine Proteinase Inhibitors; D007375:Interleukin-1; D009842:Oligopeptides; D012333:RNA, Messenger; C091530:WIN 67694; D003546:Cysteine Endopeptidases; D020170:Caspase 1