The Affiliated Eye Hospital of Nanjing Medical University, Nanjing 210029, China.
Biochem Biophys Res Commun. 2012 Aug 17;425(1):33-8. doi: 10.1016/j.bbrc.2012.07.044. Epub 2012 Jul 20.
Tumor necrosis factor-alpha (TNF-α) promotes in vitro retinal pigment epithelial (RPE) cell migration to initiate proliferative vitreoretinopathy (PVR). Here we report that TNF-α promotes human RPE cell migration by inducing matrix metallopeptidase 9 (MMP-9) expression. Inhibition of MMP-9 by its inhibitor or its neutralizing antibody inhibited TNF-α-induced in vitro RPE cell migration. Reversely, exogenously-added active MMP-9 promoted RPE cell migration. Suppression Akt/mTOR complex 1(mTORC1) activation by LY 294002 and rapamycin inhibited TNF-α-mediated MMP-9 expression. To introduce a constitutively active Akt (CA-Akt) in cultured RPE cells increased MMP-9 expression, and to block mTORC1 activation by rapamycin inhibited its effect. RNA interference (RNAi)-mediated silencing of SIN1, a key component of mTOR complex 2 (mTORC2), had no effect on MMP-9 expression or secretion. In conclusion, this study suggest that TNF-α promotes RPE cell migration by inducing MMP-9 expression through activation of Akt/ mTORC1, but not mTORC2 signaling.
肿瘤坏死因子-α（TNF-α）促进体外视网膜色素上皮（RPE）细胞迁移，从而引发增生性玻璃体视网膜病变（PVR）。在此我们报告，TNF-α通过诱导基质金属蛋白酶 9（MMP-9）表达促进人 RPE 细胞迁移。用其抑制剂或中和抗体抑制 MMP-9 可抑制 TNF-α诱导的体外 RPE 细胞迁移。相反，外源性添加的活性 MMP-9 促进了 RPE 细胞迁移。LY294002 和雷帕霉素抑制 Akt/mTOR 复合物 1（mTORC1）的激活可抑制 TNF-α介导的 MMP-9 表达。在培养的 RPE 细胞中引入组成型激活的 Akt（CA-Akt）可增加 MMP-9 的表达，而雷帕霉素抑制 mTORC1 的激活可抑制其作用。RNA 干扰（RNAi）介导的 SIN1 沉默，mTOR 复合物 2（mTORC2）的关键组成部分，对 MMP-9 的表达或分泌没有影响。总之，本研究表明，TNF-α 通过激活 Akt/mTORC1 而不是 mTORC2 信号通路诱导 MMP-9 表达，从而促进 RPE 细胞迁移。
