Autophagy attenuates the catabolic effect during inflammatory conditions in nucleus pulposus cells, as sustained by NF-κB and JNK inhibition.
Autophagy attenuates the catabolic effect during inflammatory conditions in nucleus pulposus cells, as sustained by NF-κB and JNK inhibition.
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DOI：
10.3892/ijmm.2015.2280
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发表时间：
2015-09
影响因子：
5.4
通讯作者：
Ye W
中科院分区：
文献类型：
--
作者：
Xu K;Chen W;Wang X;Peng Y;Liang A;Huang D;Li C;Ye W
导致椎间盘（IVD）退变发病机制的蛋白多糖降解是由炎症细胞因子诱导的，例如肿瘤坏死因子-α（TNF-α）和白细胞介素-1β（IL-1β）。细胞自噬存在于退行性疾病中，包括骨关节炎和椎间盘退变。然而，TNF-α和IL-1β诱导的自噬及其相应的分子机制似乎具有细胞类型依赖性。 TNF-α和IL-1β在IVD中调节自噬的作用和机制尚不清楚。此外，自噬对炎症条件下分解代谢作用的影响也仍然难以捉摸。在本研究中，使用自噬激活剂和抑制剂来证明自噬对TNF-α诱导的分解代谢效应的影响。在大鼠髓核 (NP) 细胞中，自噬的关键作用被确定：自噬的抑制会抑制细胞因子的分解代谢作用，而自噬的激活会增强细胞因子的分解代谢作用。随后，通过免疫荧光、定量聚合酶链反应和蛋白质印迹分析观察TNF-α和IL-1β处理后大鼠NP细胞中自噬相关基因的表达。然而，没有任何协会在场。此外，利用核因子κB（NF-κB）、c-Jun N末端激酶（JNK）、细胞外信号调节激酶和p38丝裂原激活蛋白激酶抑制剂以及TNF-α来确定炎症条件下自噬的分子机制，发现只有NF-κB和JNK抑制剂能够增强大鼠NP细胞的自噬。最后，利用IKKβ敲低进一步证实了NF-κB信号对人NP细胞自噬的影响，数据显示IKKβ敲低上调了炎症条件下NP细胞的自噬。
Proteoglycan degradation contributing to the pathogenesis of intervertebral disc (IVD) degeneration is induced by inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). Cell autophagy exists in degenerative diseases, including osteoarthritis and inter-vertebral disc degeneration. However, the autophagy induced by TNF-α and IL-1β and the corresponding molecular mechanism appear to be cell-type dependent. The effect and mechanism of autophagy regulated by TNF-α and IL-1β in IVDs remains unclear. Additionally, the impact of autophagy on the catabolic effect in inflammatory conditions also remains elusive. In the present study, autophagy activator and inhibitor were used to demonstrate the impact of autophagy on the catabolic effect induced by TNF-α. A critical role of autophagy was identified in rat nucleus pulposus (NP) cells: Inhibition of autophagy suppresses, while activation of autophagy enhances, the catabolic effect of cytokines. Subsequently, the autophagy-related gene expression in rat NP cells following TNF-α and IL-1β treatment was observed using immunofluorescence, quantitative polymerase chain reaction and western blot analysis; however, no association was present. In addition, nuclear factor κB (NF-κB), c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinases and p38 mitogen-activated protein kinase inhibitors and TNF-α were used to determine the molecular mechanism of autophagy during the inflammatory conditions, and only the NF-κB and JNK inhibitor were found to enhance the autophagy of rat NP cells. Finally, IKKβ knockdown was used to further confirm the effect of the NF-κB signal on human NP cells autophagy, and the data showed that IKKβ knockdown upregulated the autophagy of NP cells during inflammatory conditions.