TGF-β1 suppresses CCL3/4 expression through the ERK signaling pathway and inhibits intervertebral disc degeneration and inflammation-related pain in a rat model.
TGF-β1 suppresses CCL3/4 expression through the ERK signaling pathway and inhibits intervertebral disc degeneration and inflammation-related pain in a rat model.
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TGF-β1 通过 ERK 信号通路抑制 CCL3/4 表达并抑制大鼠模型中的椎间盘退变和炎症相关疼痛
DOI：
10.1038/emm.2017.136
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发表时间：
2017-09-22
影响因子：
12.8
通讯作者：
Zheng Z
中科院分区：
文献类型：
--
作者：
Zhang J;Li Z;Chen F;Liu H;Wang H;Li X;Liu X;Wang J;Zheng Z
本研究旨在探讨TGF-β1对椎间盘退变（IVDD）过程中CCL 3/4表达及炎症相关疼痛的调节作用。采用qPCR和免疫组化方法检测TGF-β1和CCL 3/4在不同退变髓核组织中的表达，并采用qPCR、ELISA和免疫荧光法检测TGF-β1对CCL 3/4表达的影响。采用siRNA、Western blotting和qPCR技术研究NF-κB和MAPK在TGF-β1介导的CCL 3/4启动子活性中的作用。在体内建立IVDD大鼠模型后，我们给予椎间盘内注射TGF-β1。通过MRI和组织学分析观察TGF-β1对IVDD的影响，通过免疫组化染色和疼痛行为试验观察TGF-β1对背根神经节（DRG）炎症和疼痛发展的影响。TGF-β1和CCL 3/4在退变的NP组织中表达升高。TGF-β1可显著抑制CCL 4的表达。ERK 1/2信号的药理学抑制或siRNA敲低减弱了TGF-β1介导的CCL 4表达抑制。在体内，TGF-β1注射抑制IVDD模型中退行性特征的发展。此外，TGF-β1可防止炎症反应和疼痛的发展。本研究的结果表明，TGF-β1通过激活ERK 1/2信号通路下调NP细胞中CCL 4的表达。此外，TGF-β1可以预防退行性过程，抑制DRG中的炎症反应，并预防IVDD大鼠模型中的疼痛发展。本研究的结果表明，TGF-β1可能是控制与IVDD相关的炎症相关疼痛的治疗靶点。
The objective of this study was to investigate the regulatory effects of TGF-β1 on CCL3/4 expression and inflammation-related pain during intervertebral disc degeneration (IVDD). TGF-β1 and CCL3/4 expression patterns in different degenerative human nucleus pulposus (NP) tissues were measured by qPCR and immunohistochemistry (IHC), and the effects of TGF-β1 on CCL3/4 expression were measured by qPCR, ELISA and immunofluorescence. The roles of NF-κB and MAPK in TGF-β1-mediated CCL3/4 promoter activity were studied using siRNAs, western blotting and qPCR. After establishing an IVDD rat model in vivo, we administered intradiscal injections of TGF-β1. The effects of TGF-β1 on IVDD were determined by MRI and histological analyses, and the effects of TGF-β1 on dorsal root ganglion (DRG) inflammation and pain development were determined by IHC staining and pain-behavior testing, respectively. TGF-β1 and CCL3/4 expression was elevated in degenerative NP tissue. CCL4 expression was significantly inhibited by TGF-β1 treatment. Pharmacological inhibition or siRNA knockdown of the ERK1/2 signaling attenuated TGF-β1-mediated suppression of CCL4 expression. In vivo, TGF-β1 injection inhibited the development of degenerative features in the IVDD model. Moreover, TGF-β1 prevented the inflammatory response and pain development. The results of this study show that TGF-β1 downregulates CCL4 expression through ERK1/2 signaling activation in NP cells. Furthermore, TGF-β1 can prevent degenerative processes, inhibit inflammatory responses in the DRG and prevent pain development in the IVDD rat model. The results of this study indicate that TGF-β1 may represent a therapeutic target for the control of inflammation-related pain associated with IVDD.
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