TNF-α upregulates HIF-1α expression in pterygium fibroblasts and enhances their susceptibility to VEGF independent of hypoxia
TNF-α upregulates HIF-1α expression in pterygium fibroblasts and enhances their susceptibility to VEGF independent of hypoxia
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DOI：
10.1016/j.exer.2017.08.008
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发表时间：
2017-11-01
影响因子：
3.4
通讯作者：
Kim, Jae Chan
中科院分区：
文献类型：
--
作者：
Kim, Kyoung Woo;Lee, Soo Jin;Kim, Jae Chan
翼状胬肉的临床表现以快速生长和术后复发为特征。我们以前曾提出，缺氧诱导因子（HIF）-1 α招募在翼状胬肉的发展和进展的祖细胞。最近，据报道，各种刺激，包括炎症，可以激活HIF-1 α，即使在常氧条件下。眼表面直接面对外部环境，因此经常暴露于炎性损伤。首先，我们检测了HIF-1 α、其下游分子、血管内皮生长因子（VEGF）-A和VEGF受体（VEGFR）-2在角膜和结膜细胞中的基因表达，并与培养的人脐静脉内皮细胞进行比较。在TNF-α存在下，角膜成纤维细胞具有VEGFR-2的高表达，并且HIF-1 α在多种眼表面细胞中被TNF-α激活。在培养的人翼状胬肉成纤维细胞（HPF）中，在基因和蛋白质水平上评估了响应于TNF-α的HIF-1 α/VEGF/VEGFR信号传导途径，并与用氯化钴（CoCl 2）（一种低氧模拟物）治疗进行比较，以排除低氧的影响。尽管VEGF-A表达不受TNF-α的影响，但HIF-1 α和VEGFR-2的表达在用TNF-α处理的HPF中增强，与缺氧条件无关。此外，VEGF-C基因表达仅被HPF中的TNF-α激活，但VEGF-B水平未受到显著影响。这些结果可能提供了在TNF-α诱导的眼表炎症过程中翼状胬肉纤维血管组织独特的剧烈增殖的机制解释。(C)2017爱思唯尔有限公司版权所有
The clinical manifestations of pterygium are characterized by rapid growth and postoperative recurrences. We had previously proposed that hypoxia-inducible factor (HIF)-l alpha recruits progenitor cells during the development and progression of pterygia. Recently, it was reported that various stimuli, including inflammation, could activate HIF-l alpha even under normoxic conditions. The ocular surface directly faces external environments, and is thus frequently exposed to inflammatory insults. First, we examined the gene expression of HIF-la, its downstream molecule, vascular endothelial growth factor (VEGF)-A, and VEGF receptor (VEGFR)-2 in corneal and conjunctival cells compared with cultured human umbilical vein endothelial cells. Corneal fibroblasts had high expression of VEGFR-2 in the presence of TNF-alpha, and HIF-l alpha was activated by TNF-alpha in diverse ocular surface cells. The HIF-l alpha/VEGF/VEGFR signaling pathway in response to TNF-alpha was evaluated in cultured human pterygium fibroblasts (HPFs) at the gene and protein levels and was compared to treatment with cobalt chloride (CoCl2), a hypoxic mimetic, to exclude the effect of hypoxia. Although VEGF-A expression was not changed by TNF-alpha, expression of HIF-la and VEGFR-2 was enhanced in HPFs treated with TNF-a, independent of hypoxia conditioning. In addition, VEGF-C gene expression was activated solely by TNF-alpha in HPF, but VEGF-B levels were not significantly affected. These results may provide mechanistic explanations for the uniquely vigorous proliferation of pterygium fibrovascular tissue during TNF-alpha-induced ocular surface inflammation. (C) 2017 Elsevier Ltd. All rights reserved.