Fletcher D S, Agarwal L, Chapman K T, Chin J, Egger L A, Limjuco G, Luell S, MacIntyre D E, Peterson E P, Thornberry N A
Merck Research Laboratories, Rahway, NJ 07065, USA.
J Interferon Cytokine Res. 1995 Mar;15(3):243-8. doi: 10.1089/jir.1995.15.243.
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.
一种强效、可逆的白细胞介素-1β转化酶（ICE）四肽抑制剂L-709,049已被证明可抑制成熟IL-1β的体外产生。我们现在报告，这种抑制剂在小鼠内毒素休克模型中也能有效抑制成熟IL-1β的产生。腹腔注射L-709,049可使经脂多糖（LPS）处理的小鼠血浆和腹腔液中IL-1β的升高呈剂量相关下降（半数有效剂量[ED50]=2±0.9毫克/千克）。这些小鼠中LPS诱导的IL-1α和IL-6升高不受影响，表明该抑制剂特异性影响IL-1β的产生。血浆和腹腔液的免疫印迹分析表明，L-709,049在体内抑制了成熟IL-1β的产生。当将小鼠血液与LPS在体外孵育时，IL-1β释放到血浆中。该试验用于在给小鼠施用ICE抑制剂后离体测定其在血液中的活性。给小鼠腹腔注射10毫克/千克L-709,049后15分钟获得的血液产生的IL-1β比对照血液少80%，并且在注射该抑制剂30分钟后获得的血液中IL-1β产生恢复到对照水平。此外，从这些动物获得的血浆防止ICE切割合成底物的能力在腹腔注射50毫克/千克抑制剂后1小时内消失。
