Role of macrophage migration inhibitory factor (MIF) in the effects of oxidative stress on human retinal pigment epithelial cells
Role of macrophage migration inhibitory factor (MIF) in the effects of oxidative stress on human retinal pigment epithelial cells
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DOI：
10.1002/cbf.3292
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发表时间：
2017-10-01
影响因子：
3.6
通讯作者：
Kiuchi, Yoshiaki
中科院分区：
文献类型：
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作者：
Ko, Ji-Ae;Sotani, Yasuyuki;Kiuchi, Yoshiaki
复发性玻璃体视网膜病变（PVR）是视网膜脱离手术治疗失败的主要原因。视网膜色素上皮（RPE）细胞的上皮间质转化（EMT）参与了PVR的发病机制。氧化应激被认为在包括PVR在内的视网膜疾病的进展中起作用。我们现在已经研究了氧化应激对人RPE细胞系中EMT和相关过程的影响。我们发现，过氧化氢诱导的三维胶原凝胶中的RPE细胞的收缩。细胞因子阵列的分析显示，H2 O2特异性地增加了RPE细胞释放巨噬细胞移动抑制因子（MIF）。逆转录-聚合酶链反应和免疫印迹分析表明，H2 O2增加了MIF在RPE细胞中的表达。免疫印迹和免疫荧光分析显示，H2 O2上调-SMA和波形蛋白的表达，下调ZO-1和N-cadherin的表达。与这些观察结果一致，细胞的跨上皮电阻通过暴露于H2 O2而降低。氧化应激对EMT相关蛋白和连接蛋白表达以及跨上皮电阻的影响被MIF抗体抑制，但它们不能被重组MIF治疗所模仿。最后，分析与有丝分裂原活化蛋白激酶信号分析阵列显示，过氧化氢特异性诱导p38有丝分裂原活化蛋白激酶的磷酸化。因此，我们的研究结果表明，MIF可能发挥作用，诱导EMT和相关过程中的氧化应激在RPE细胞，它可能因此有助于PVR的发病机制。破坏性玻璃体视网膜病变是孔源性视网膜脱离的主要并发症，氧化应激和RPE细胞中EMT的诱导被认为有助于这种病症的发病机制。我们现在已经研究了氧化应激对人RPE细胞系ARPE 19中EMT和相关过程的影响。因此，我们的研究结果暗示MIF诱导EMT和相关过程中的氧化应激在RPE细胞和EMT标志物的表达调控。提示MIF可能在PVR的发病机制中起重要作用。
Proliferative vitreoretinopathy (PVR) is the major cause of treatment failure in individuals who undergo surgery for retinal detachment. The epithelial-mesenchymal transition (EMT) in retinal pigment epithelium (RPE) cells contributes to the pathogenesis of PVR. Oxidative stress is thought to play a role in the progression of retinal diseases including PVR. We have now examined the effects of oxidative stress on the EMT and related processes in the human RPE cell line. We found that H2O2 induced the contraction of RPE cells in a three-dimensional collagen gel. Analysis of a cytokine array revealed that H2O2 specifically increased the release of macrophage migration inhibitory factor (MIF) from RPE cells. Reverse transcription-polymerase chain reaction and immunoblot analyses showed that H2O2 increased the expression of MIF in RPE cells. Immunoblot and immunofluorescence analyses revealed that H2O2 upregulated the expression of -SMA and vimentin and downregulated that of ZO-1 and N-cadherin. Consistent with these observations, the transepithelial electrical resistance of cell was reduced by exposure to H2O2. The effects of oxidative stress on EMT-related and junctional protein expression as well as on transepithelial electrical resistance were inhibited by antibodies to MIF, but they were not mimicked by treatment with recombinant MIF. Finally, analysis with a profiling array for mitogen-activated protein kinase signalling revealed that H2O2 specifically induced the phosphorylation of p38 mitogen-activated protein kinase. Our results thus suggest that MIF may play a role in induction of the EMT and related processes by oxidative stress in RPE cells and that it might thereby contribute to the pathogenesis of PVR. Proliferative vitreoretinopathy is a major complication of rhegmatogenous retinal detachment, and both oxidative stress and induction of the EMT in RPE cells are thought to contribute to the pathogenesis of this condition. We have now examined the effects of oxidative stress on the EMT and related processes in the human RPE cell line ARPE19. Our results thus implicate MIF in induction of the EMT and related processes by oxidative stress in RPE cells and the regulated expression of EMT markers. They further suggest that MIF may play an important role in the pathogenesis of PVR.