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首页> 外文期刊>Cellular Physiology and Biochemistry >Butein Activates Autophagy Through AMPK/TSC2/ULK1/mTOR Pathway to Inhibit IL-6 Expression in IL-1β Stimulated Human Chondrocytes
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Butein Activates Autophagy Through AMPK/TSC2/ULK1/mTOR Pathway to Inhibit IL-6 Expression in IL-1β Stimulated Human Chondrocytes

机译：Butein通过AMPK / TSC2 / ULK1 / mTOR途径激活自噬，抑制IL-1β刺激的人软骨细胞中IL-6的表达。

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Background/Aims Butein (2’,3,4,4’-Tetrahydroxychalcone), a polyphenol produced by several plants including Butea monoserpma, has been reported to exert potent anti-inflammatory activity but the mechanism remains unknown. In the present work we investigated the mechanism of Butein-mediated suppression of IL-6 expression in normal and human osteoarthritis (OA) chondrocytes under pathological conditions. Methods Expression level of interleukin-6 (IL-6) protein in OA cartilage was analyzed by immunohistochemistry using a validated antibody. Chondrocytes derived from normal or OA cartilage by enzymatic digestion were pretreated with Butein followed by stimulation with interleukin-1β (IL-1β) and the levels of IL-6 mRNA were quantified by TaqMan assay and the protein levels were measured by Western immunoblotting. Autophagy activation was determined by Western blotting and confocal microscopy. Autophagy was inhibited by siRNA mediated knockdown of ATG5. Results Expression of IL-6 protein was high in the OA cartilage compared to smooth cartilage from the same patient. OA chondrocytes and cartilage explants stimulated with IL-1β showed high level expression of IL-6 mRNA and protein. Butein increased the phosphorylation of AMPKαThr-172, TSC2Ser-1387 and ULK1Ser-317 and inhibited the phosphorylation of mTORSer-2448 and its downstream target p70S6K and increased autophagy flux that correlated with the suppression of the IL-1β mediated expression of IL-6 in normal and OA chondrocytes. In OA chondrocytes with siRNA-mediated knockdown of ATG5 expression, treatment with Butein failed to activate autophagy and abrogated the suppression of IL-1β induced IL-6 expression. Conclusion Our findings demonstrate for the first time that Butein activate autophagy in OA chondrocytes via AMPK/TSC2/ULK1/mTOR pathway. Additionally, activation of autophagy was essential to block the IL-1β-induced expression of IL-6 in OA chondrocytes. These data support further studies to evaluate the use of Butein or compounds derived from it for the management of OA.
机译：背景/目的据报道，丁香（2'，3,4,4'-四羟基查尔酮）是由包括丁香丁香在内的几种植物产生的多酚，具有有效的抗炎活性，但其机理尚不清楚。在本工作中，我们研究了Butein介导的在病理条件下正常和人骨关节炎（OA）软骨细胞中IL-6表达抑制的机制。方法采用经过验证的抗体，通过免疫组织化学分析白细胞介素6（IL-6）蛋白在OA软骨中的表达水平。用Butein预处理通过酶消化从正常或OA软骨衍生的软骨细胞，然后用白介素-1β（IL-1β）刺激，通过TaqMan测定定量IL-6 mRNA的水平，并通过Western免疫印迹法测定蛋白质的水平。通过Western印迹和共聚焦显微镜确定自噬激活。自噬被siRNA介导的ATG5敲低抑制。结果与同一患者的平滑软骨相比，OA软骨中IL-6蛋白的表达较高。 IL-1β刺激的OA软骨细胞和软骨外植体高水平表达IL-6 mRNA和蛋白。 Butein增加AMPKαThr-172，TSC2Ser-1387和ULK1Ser-317的磷酸化，并抑制mTORSer-2448及其下游靶标p70S6K的磷酸化，并增加自噬通量，这与抑制IL-1β介导的IL-6表达有关。正常和OA软骨细胞。在具有siRNA介导的ATG5表达敲低的OA软骨细胞中，用Butein处理无法激活自噬，并废除了抑制IL-1β诱导的IL-6表达。结论我们的发现首次证明Butein通过AMPK / TSC2 / ULK1 / mTOR途径激活OA软骨细胞的自噬。另外，自噬的激活对于阻断IL-1β诱导的OA软骨细胞中IL-6的表达至关重要。这些数据支持进一步的研究，以评估Butein或衍生自Butein的化合物在OA管理中的用途。

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