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Jae Chan Kim, Joonhyung Yeo, Soo Jin Lee, Kyoung Woo Kim; TNF-α upregulates HIF-1α expression in pterygium fibroblasts and enhances their susceptibility to VEGF independent of hypoxia. Invest. Ophthalmol. Vis. Sci. 2017;58(8):1401.
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The clinical manifestations of pterygium are characterized by rapid growth and postoperative recurrences. We previously proposed that hypoxia-inducible factor (HIF)-1α recruits progenitor cells during the development and progression of pterygia. We tested the hypothesis that TNF-α induced inflammation may upregulate HIF-1α production in pterygial cells and further induce proteins involved in angiogenesis and vascular remodeling, such as VEGF using an experimental cell of cornea and conjunctiva.
Human umbilical vein endothelial cells (HUVECs), Human corneal epithelial cells (HCEpCs), Human corneal fibroblasts (HCFs), Human corneal endothelial cells (HCEnCs), Human conjunctival fibroblasts (HCJFs), and Human pterygium fibroblasts (HPFs) were treated with TNF-α (300-01, PeproTech, Rocky Hill, NJ, USA) at a concentration of 20 ng/mL for 24 hours to induce NF-κB activation for inflammation. The same cells were treated with cobalt (II) chloride (CoCl2; 15862, Sigma-Aldrich), which is a well-known hypoxia mimetic and a strong inducer of HIF-1α, at a concentration of 100 μM for 24 hours for hypoxia conditioning.
Treatment of HPFs with TNF-α for 24 hours significantly upregulated HIF-1α mRNA and protein expression. However, hypoxic conditioning with CoCl2 treatment for 24 hours did not activate HIF-1α at all, and even unexpectedly suppressed HIF-1α at the mRNA level, as in HUVECs, HCEpCs, HCFs, HCEnCs, and HCJFs. And to investigate whether TNF-α affects the susceptibility of HPFs to VEGF, we analyzed VEGFR-1 and VEGFR-2 expression in cultured HPFs treated with TNF-α or CoCl2. VEGFR-1 expression did not change in response to either TNF-α or CoCl2 at both mRNA and protein expression levels. However, TNF-α significantly upregulated both mRNA and protein expression of VEGFR-2.
HPFs exhibited marked increases in the expression of HIF-1α and VEGFR-2 upon stimulation with TNF-α independent of hypoxia. TNF-α antagonist is likely to be effective against the stromal proliferation of pterygia.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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