TAK-242 selectively suppresses Toll-like receptor 4-signaling mediated by the intracellular domain
TAK-242 selectively suppresses Toll-like receptor 4-signaling mediated by the intracellular domain
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DOI：
10.1016/j.ejphar.2008.01.026
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发表时间：
2008-04-14
影响因子：
5
通讯作者：
Kimura, Hiroyuki
中科院分区：
文献类型：
--
作者：
Kawamoto, Tomohiro;Ii, Masayuki;Kimura, Hiroyuki
Tak-242是一种小分子防腐剂，已被证明可以抑制脂多糖(LPS)诱导的炎症。在这项研究中，我们证明了TAK-242是Toll样受体(TLR)-4信号的选择性抑制剂。Tak-242几乎完全抑制TLR4特异性配体--超纯脂多糖诱导RAW264.7、人U-937和p31/FUJ细胞产生一氧化氮(NO)或肿瘤坏死因子-α，而对其他TLR配体Pam(3)、CSK(4)(TLR1/2)、肽聚糖(TLR2/6)、双链RNA(TLR3)、R-848(TLR7)和CpG寡核苷酸(TLR9)几乎没有影响。此外，TAK-242能有效抑制超纯脂多糖诱导的HEK293细胞核因子-kappaB活化，瞬时表达TLR4及其辅受体、髓系分化蛋白-2(MD2)和CD14，而对其他TLR、TLR1/2、TLR2/6、TLR3、TLR5、TLR7和TLR9无明显影响。Tak-242还抑制TLR4过表达引起的非配体依赖的核因子-kappaB的激活。尽管由人或鼠TLR4的胞外区和胞内区组成的嵌合体受体显示出结构性的核因子-kappa B激活，但Tay-242有效地抑制了来自CD4-TLR4嵌合体受体的信号。而TLR4接头、髓系分化因子88(MyD88)、TIR相关蛋白(TERAP)、含Toll/IL-1R同源(TIR)结构域的接头蛋白诱导干扰素-p(TRIF)或TRIF相关接头分子(TRAM)介导的核因子-kappaB的活化不受TAK-242的影响。因此，Tak-242是TLR4胞内区信号的选择性抑制剂，代表了治疗TLR4介导的疾病的一种新的治疗方法。(C)2008爱思唯尔B.V.保留所有权利。
TAK-242, a small-molecule antisepsis agent, has shown to suppress lipopolysaccharide (LPS)-induced inflammation. In this study, we demonstrate that TAK-242 is a selective inhibitor of Toll-like receptor (TLR)-4 signaling. TAK-242 almost completely suppressed production of nitric oxide (NO) or tumor necrosis factor (TNF)-alpha induced by a TLR4-specific ligand, ultra-pure LPS, in mouse RAW264.7, human U-937 and P31/FUJ cells, whereas this agent showed little effect on other TLR ligands, Pam(3)CSK(4) (TLR1/2), peptidoglycan (TLR2/6), double strand RNA (TLR3), R-848 (TLR7) and CpG oligonucleotide (TLR9). Furthermore, TAK-242 potently inhibited nuclear factor (NF)-kappa B activation induced by ultra-pure LPS in HEK293 cells transiently expressing TLR4 and co-receptors, myeloid differentiation protein-2 (MD2) and CD14, whereas this agent showed little effect on other TLRs, TLR1/2, TLR2/6, TLR3, TLR5, TLR7 and TLR9. TAK-242 also inhibited ligand-independent NF-kappa B activation resulting from over-expression of TLR4. Although chimera receptors, which are consist of the extracellular domain of CD4 and the intracellular domain of human or mouse TLR4, showed constitutive NF-kappa B activation, TAY-242 potently inhibited the signaling from CD4-TLR4 chimera receptors. In contrast, the NF-kappa B activation mediated by TLR4 adaptors, myeloid differentiation factor 88 (MyD88), TIR-associated protein (TERAP), Toll/IL-1R homology (TIR)-domain-containing adaptor protein-inducing interferon-p (TRIF) or TRIF-related adaptor molecule (TRAM) was not affected by TAK-242. TAK-242 is therefore a selective inhibitor of signaling from the intracellular domain of TLR4 and represents a novel therapeutic approach to the treatment of TLR4-mediated diseases. (c) 2008 Elsevier B.V. All rights reserved.