The TRIF/TBK1/IRF-3 activation pathway is the primary inhibitory target of resveratrol, contributing to its broad-spectrum anti-inflammatory effects
The TRIF/TBK1/IRF-3 activation pathway is the primary inhibitory target of resveratrol, contributing to its broad-spectrum anti-inflammatory effects
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DOI：
10.1691/ph.2011.0798
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发表时间：
2011-04-01
期刊：
影响因子：
1.6
通讯作者：
Cho, Jae Youl
中科院分区：
文献类型：
--
作者：
Kim, Min Ho;Yoo, Dae Sung;Cho, Jae Youl
白藜芦醇是葡萄酒和果汁中发现的一种二苯乙烯类化合物，具有抗氧化、抗癌、抗炎和抗衰老等多种药理活性。虽然许多论文已经探索了白藜芦醇在一个特定的细胞作用的药理学，但这种化合物如何同时具有多种作用尚未完全解决。因此，在这项研究中，我们探讨了其广谱的抑制机制，使用脂多糖（LPS）介导的炎症反应和报告基因检测涉及过表达的Toll样受体（TLR）衔接分子。共转染衔接子分子如（1）髓样分化初级应答基因88（MyD 88），（2）Toll/4 II-1含有衔接子结构域的诱导干扰素-β（TRIF），（3）TRIF相关衔接子分子（TRAM），或（4）TANK结合激酶（TBK）1强烈增强了由转录因子介导的荧光素酶活性，所述转录因子包括核因子（NF）-κ B，激活蛋白（AP）-1和干扰素调节因子（IRF）-3。在衔接蛋白中，TRIF和TBK 1增强了这些转录因子介导的荧光素酶活性，而MyD 88和IKK没有增强。白藜芦醇剂量依赖性地抑制LPS诱导的巨噬细胞NO的产生。它还阻断了LPS诱导的IFN-β、肿瘤坏死因子（TNF）-α和诱导型一氧化氮合酶（iNOS）mRNA水平的增加。白藜芦醇在90 min时抑制IRF-3的移位或激活，在120 min时抑制AP-1亚基c-Jun和STAT-1的移位或激活，在60和90 min时抑制NF-κ B亚基p50的移位或激活。白藜芦醇强烈抑制这些衔接子分子诱导的荧光素酶活性上调，IC 50值为5 - 65 μ M。特别地，当TRIF或TBK 1在荧光素酶构建体与IRF-3结合序列共转染后过表达时，白藜芦醇的抑制作用更高。总之，我们的数据表明，TRIF和TBK 1的抑制，介导NF-κ B，AP-1和IRF-3的转录激活，有助于白藜芦醇的广谱抑制活性，这种化合物可以进一步开发为一种领先的抗炎化合物。
Resveratrol, a stilbene type compound identified in wine and fruit juice, has been found to exhibit various pharmacological activities such as anti-oxidative, anti-cancerous, anti-inflammatory and anti-aging effects. Although numerous papers have explored the pharmacology of resveratrol in one particular cellular action, how this compound can have multiple effects simultaneously has not been fully addressed. In this study, therefore, we explored its broad-spectrum inhibitory mechanism using lipopolysaccharide (LPS)-mediated inflammatory responses and reporter gene assays involving overexpression of toll like receptor (TLR) adaptor molecules. Co-transfection of adaptor molecules such as (1) myeloid differentiation primary response gene 88 (MyD88), (2) Toll/4II-1 Receptor-domain-containing adapter-inducing interferon-beta (TRIF), (3) TRIF-related adaptor molecule (TRAM), or (4) TANK-binding kinase (TBK) 1 strongly enhanced luciferase activity mediated by transcription factors including nuclear factor (NF)-kappa B, activator protein (AP)-1, and interferon regulatory factor (IRF)-3. Of the adaptor proteins, TRIF and TBK1 but not MyD88 and IKK enhanced luciferase activity mediated by these transcription factors. Resveratrol dose-dependently suppressed LPS-induced NO production in macrophages. It also blocked the increases in levels of mRNA for IFN-beta, tumor necrosis factor (TNF)-alpha, and inducible nitric oxide synthase (iNOS) that were induced by LPS. Resveratrol diminished the translocation or activation of IRF-3 at 90 min, c-Jun, a subunit of AP-1, and STAT-1 at 120 min, and p50, a subunit of NF-kappa B, at 60 and 90 min. Resveratrol strongly suppressed the up-regulation of luciferase activity induced by these adaptor molecules with IC50 values of 5 to 65 p,M. In particular, higher inhibitory effects of resveratrol were when TRIF or TBK1 were overexpressed following cotransfection of luciferase constructs with IRF-3 binding sequences. Taken together, our data suggest that the suppression of TRIF and TBK1, which mediates transcriptional activation of NF-kappa B, AP-1, and IRF-3, contributes to resveratrol's broad-spectrum inhibitory activity, and that this compound can be further developed as a lead anti-inflammatory compound.