TNF-alpha upregulates HIF-1 alpha expression in pterygium fibroblasts and enhances their susceptibility to VEGF independent of hypoxia

초록

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.

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