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Salubrinal Suppresses IL-17-Induced Upregulation of MMP-13 and Extracellular Matrix Degradation Through the NF-kB Pathway in Human Nucleus Pulposus Cells

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Abstract

Matrix metalloproteinase 13 (MMP-13) plays an important role in the process of pro-inflammatory cytokine-induced intervertebral disc degeneration (IDD). This study examined the effect of IL-17 on the regulation of MMP-13 and the extracellular matrix (ECM) in the intervertebral disc (IVD). We then examined whether salubrinal, a known inhibitor of eIF2α dephosphorylation, inhibited the IL-17-induced changes mentioned above. Furthermore, we demonstrated a potential therapeutic role for salubrinal in alleviating the chronic inflammatory-dependent degenerative state commonly observed in IDD. After inflammatory distress with IL-17, RT-PCR and western blot were employed to investigate the expression of MMP-13, collagen type II (COL2A1), collagen type I (COL1A1), and aggrecan (ACAN) in nucleus pulpous (NP) tissue. Activation of the NF-kB pathway was measured by western blot and immunocytochemistry following IL-17 treatment. We also examine the level of eIF2α phosphorylation after IL-17 treatment with or without salubrinal. Then, we investigated interactions of the NF-kB pathway to eIF2α phosphorylation. Moreover, we employed salubrinal and a specific inhibitor of NF-kB (BAY11-7082) to evaluate their effects on IL-17-driven regulation of MMP-13 and the ECM, as well as on the activation of NF-kB. The results showed that IL-17 increased the production of MMP-13 and decreased expression of COL2A1 and ACAN via the NF-kB pathway. Either IL-17 or salubrinal increased the level of eIF2α phosphorylation, but the effects of BAY11-7082 on the level of p-eIF2α were not detectable. BAY11-7082 and salubrinal significantly suppressed IL-17-driven intervertebral disc degeneration. Furthermore, salubrinal produced stronger effects than BAY11-7082. These results imply the potential involvement of IL-17 in IDD through activation of NF-kB signaling, which successively upregulated the expression of MMP-13 and led to the degradation of the ECM. Furthermore, salubrinal can inhibit this process through inhibition of NF-kB activation that is not directly linked to eIF2α phosphorylation, suggesting a potential therapeutic role in IDD.

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Acknowledgments

The study was supported by grants from the Natural Science Foundation of Shandong Province (ZR2013HM095) and the National Natural Science Foundation of China (81572191, 81501880).

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Authors and Affiliations

  1. Department of Orthopedics, Qilu Hospital of Shandong University, Jinan, 250012, China

    Zhixiao Yao, Lin Nie, Yunpeng Zhao, Yuanqiang Zhang, Yi Liu, Jingkun Li & Lei Cheng

  2. The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan, 250012, People’s Republic of China

    Zhixiao Yao

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  1. Zhixiao Yao
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Yao, Z., Nie, L., Zhao, Y. et al. Salubrinal Suppresses IL-17-Induced Upregulation of MMP-13 and Extracellular Matrix Degradation Through the NF-kB Pathway in Human Nucleus Pulposus Cells. Inflammation 39, 1997–2007 (2016). https://doi.org/10.1007/s10753-016-0435-y

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