Bikunin suppresses expression of pro-inflammatory cytokines induced by lipopolysaccharide in neutrophils
Bikunin suppresses expression of pro-inflammatory cytokines induced by lipopolysaccharide in neutrophils
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DOI：
10.1177/0968051907086464
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发表时间：
2007-01-01
期刊：
影响因子：
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通讯作者：
Kobayashi, Hiroshi
中科院分区：
文献类型：
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作者：
Kanayama, Seiji;Yamada, Yoshihiko;Kobayashi, Hiroshi
活化的中性粒细胞有助于早产的发展。由于其抑制炎症的能力，Bikunin，一种Kunitz型蛋白酶抑制剂，目前正在临床试验中。为了研究这种抑制的分子机制，我们分析了bikunin对脂多糖（LPS）（一种炎症诱导剂）刺激的小鼠中性粒细胞中促炎细胞因子产生和核因子-κ B（NF-κ B）活化的影响。在此，我们表明bikunin：（i）以剂量依赖性方式阻断LPS诱导的促炎细胞因子（包括TNF-α和IL-1 β）的分泌;（ii）在0.2 μ M浓度下对细胞因子产生具有抑制作用，在测试的最高剂量（5 μ M）下达到65%抑制;（iii）具有ERKI/2和p38信号通路的抑制能力;和（iv）依次抑制LPS诱导的I κ B-α的磷酸化、I κ B-α的降解和NF-κ B的核转位。当分析MAPK数据时，在0.2 μ M bikunin剂量下未观察到磷酸化的显著降低，但在1.0 μ M剂量下观察到。Bikunin可以抑制LPS诱导的中性粒细胞活化和细胞因子释放，尽管它不太可能主要通过抑制MAPK磷酸化起作用。这些数据表明，这种作用在体内是重要的，并在消除嗜中性粒细胞介导的炎症反应，如早产中发挥了重要的贡献作用。
Activated neutrophils contribute to the development of preterm delivery. Because of its ability to suppress inflammation, bikunin, a Kunitz-type protease inhibitor, is currently in clinical trials. To investigate the molecular mechanism of this inhibition, we analyzed the effect of bikunin on pro-inflammatory cytokine production and nuclear factor-kappaB (NF-kappa B) activation in mouse neutrophils stimulated by lipopolysaccharide (LPS), an inflammatory inducer. Here, we show that bikunin: (i) blocks LPS-induced secretion of pro-inflammatory cytokines, including TNF-alpha and IL-1 beta, in a dose-dependent manner; (ii) has an inhibitory effect on cytokine production at a concentration of 0.2 mu M, reaching 65% inhibition at the highest doses of bikunin tested (5 mu M); (iii) has the suppressive capacity of ERKI/2 and p38 signaling pathways; and (iv) inhibited sequentially the LPS-induced phosphorylation of I kappa B-alpha, degradation of I kappa B-alpha, and nuclear translocation of NF-kappa B. When the MAPK data are analyzed, a significant decrease in phosphorylation is not seen at 0.2 mu M bikunin but is at 1.0 mu M dosing. Bikunin can inhibit LPS-induced neutrophil activation and cytokine release, although it is unlikely that it works primarily through the inhibition of MAPK phosphorylation. These data suggest that such effects are important in vivo and play a major contributory role in abrogation of neutrophil-mediated inflammatory responses, such as preterm delivery.