Effect of rottlerin, a PKC-δ inhibitor, on TLR-4-dependent activation of murine microglia
Effect of rottlerin, a PKC-δ inhibitor, on TLR-4-dependent activation of murine microglia
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DOI：
10.1016/j.bbrc.2005.09.009
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发表时间：
2005-11-11
影响因子：
3.1
通讯作者：
Kim, KT
中科院分区：
文献类型：
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作者：
Kim, DC;Kim, SH;Kim, KT
在小胶质细胞中，Toll样受体已被证明识别病原体相关的分子模式，并在与感染因子相互作用后启动先天免疫应答。在脂多糖和紫杉醇刺激的小鼠小胶质细胞中研究了PKC-δ特异性抑制剂rottlerin对TLR-4介导的信号传导的影响。用rottlerin预处理小胶质细胞以浓度依赖性方式降低LPS和紫杉醇诱导的一氧化氮产生（IC 50 = 99.1 +/- 1.5 nM）。通过MTT和流式细胞仪分析，我们发现rottlerin的抑制作用不是由于小胶质细胞的死亡。Rottlerin预处理也减弱LPS诱导的IkappaB-α磷酸化、NF-κ B核转位和11型一氧化氮合酶表达。此外，经过罗特勒素预处理的小胶质细胞对TLR-4激活的吞噬作用减弱。总之，这些数据提出了某些PKC-δ特异性抑制剂可以调节TLR-4衍生的信号传导和炎症靶基因表达，并可以改变中枢神经系统对微生物感染和慢性炎症性疾病的易感性的可能性。(c)2005年爱思唯尔公司All rights reserved.
In microglia, Toll-like receptors have been shown to recognize pathogen-associated molecular patterns and initiate innate immune responses upon interaction with infectious agents. The effect of rottlerin, a PKC-delta specific inhibitor, on TLR-4-mediated signaling was investigated in murine microglia stimulated with lipopolysaccharide and taxol. Pretreatment of microglia cells with rottlerin decreased LPS- and taxol-induced nitric oxide production in a concentration-dependent manner (IC50 = 99.1 +/- 1.5 nM). Through MTT and FACS analysis, we found that the inhibition effect of rottlerin was not due to microglial cell death. Rottlerin pretreatment also attenuated LPS-induced phosphorylation of IkappaB-alpha, nuclear translocation of NF-kappa B, and expression of type 11 nitric oxide synthase. In addition, microglial phagocytosis in response to TLR-4 activation was diminished in which rottlerin was pretreated. Together, these data raise the possibility that certain PKC-delta specific inhibitors can modulate TLR-4-derived signaling and inflammatory target gene expression, and can alter susceptibility to microbial infection and chronic inflammatory diseases in central nervous system. (c) 2005 Elsevier Inc. All rights reserved.