Luteolin reduces IL-6 production in microglia by inhibiting JNK phosphorylation and activation of AP-1
Luteolin reduces IL-6 production in microglia by inhibiting JNK phosphorylation and activation of AP-1
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DOI：
10.1073/pnas.0802865105
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发表时间：
2008-05-27
影响因子：
11.1
通讯作者：
Johnson, Rodney W.
中科院分区：
文献类型：
--
作者：
Jang, Saebyeol;Kelley, Keith W.;Johnson, Rodney W.
木犀草素是一种在芹菜和青椒中发现的高浓度黄酮类化合物，已被证明可以减少内毒素刺激的巨噬细胞、成纤维细胞和肠道上皮细胞中促炎介质的产生。由于激活的脑小胶质细胞过度产生促炎细胞因子可导致行为病理和神经变性，我们试图确定木犀草素是否也调节小胶质细胞产生典型的炎性细胞因子IL-6。原代小鼠小胶质细胞和BV-2小胶质细胞用木犀草素预处理后，可在mRNA和蛋白水平上抑制脂多糖刺激的IL-6的产生。为了确定木犀草素如何抑制小胶质细胞中IL-6的产生，采用EMSA方法研究了木犀草素对内毒素诱导的转录因子与IL-6启动子上的核因子-kappaB和激活蛋白-1(AP-1)结合的影响。木犀草素对脂多糖诱导的核因子-kappaBDNA结合活性无影响，但显著降低AP-1转录因子结合活性。与这一发现一致的是，木犀草素不能抑制内毒素诱导的I kappa B-α的降解，但抑制了JNK的磷酸化。为了确定木犀草素在体内是否有类似的作用，给小鼠提供添加木犀草素的饮用水21天，然后给它们注射木犀草素。用嘴唇。注射木犀草素后4h，木犀草素可降低内毒素诱导的血浆IL-6水平。此外，木犀草素可降低内毒素诱导的大鼠海马区IL-6mRNA的表达，但对大脑皮层和小脑的诱导作用不明显。综上所述，这些数据表明木犀草素通过抑制JNK信号通路来抑制ILPS诱导的脑内IL-6的产生。小胶质细胞内AP-1的活化。因此，木犀草素可能有助于减轻神经炎症。
Luteolin, a flavonoid found in high concentrations in celery and green pepper, has been shown to reduce production of proinflammatory mediators in LPS-stimulated macrophages, fibroblasts, and intestinal epithelial cells. Because excessive production of proinflammatory cytokines by activated brain microglia can cause behavioral pathology and neurodegeneration, we sought to determine whether luteolin also regulates microglial cell production of a prototypic inflammatory cytokine, IL-6. Pretreatment of primary murine microlgia and BV-2 microglial cells with luteolin inhibited LPS-stimulated IL-6 production at both the mRNA and protein levels. To determine how luteolin inhibited IL-6 production in microglia, EMSAs were performed to establish the effects of luteolin on LPS-induced binding of transcription factors to the NF-kappa B and activator protein-1 (AP-1) sites on the IL-6 promoter. Whereas luteolin had no effect on the LPS-induced increase in NF-kappa B DNA binding activity, it markedly reduced AP-1 transcription factor binding activity. Consistent with this finding, luteolin did not inhibit LPS-induced degradation Of I kappa B-alpha but inhibited JNK phosphorylation. To determine whether luteolin might have similar effects in vivo, mice were provided drinking water supplemented with luteolin for 21 days and then they were injected i.p. with LIPS. Luteolin consumption reduced LPS-induced IL-6 in plasma 4 h after injection. Furthermore, luteolin decreased the induction of IL-6 mRNA by LPS in hippocampus but not in the cortex or cerebellum. Taken together, these data suggest luteolin inhibits ILPS-induced IL-6 production in the brain by inhibiting the JNK signaling pathway. and activation of AP-1 in microglia. Thus, luteolin may be useful for mitigating neuroinflammation.