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V. K. Kommineni, C. N. Nagineni, A. William, B. Detrick, J. J. Hooks; Interferon- Differentially Regulates the Expression of VEGF-A, VEGF-C and sVEGF-R1 in Human Corneal Epithelial and Stromal Fibroblasts. Invest. Ophthalmol. Vis. Sci. 2008;49(13):1483.
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Corneal neovascularization (CN) may lead to corneal opacity and loss of visual function. Infilteration of leukocytes is the initial event in CN suggesting the critical role of cytokines in the development of CN. We studied the effects of cytokines on the expression of vascular endothelial growth factors (VEGFs), key regulators of angiogenesis, in corneal cells.
Human corneal epithelial cell line (HCE) and primary cultures of human corneal fibroblasts (HCRF) were used in this study. Confluent cultures were treated with IFN-γ, TNF-α, IL-1 alone or in combinations, and TGF-β in serum free medium for 24 h. Culture supernatants were used for the analysis of secreted VEGF-A, VEGF-C, VEGF-D, sVEGF-R1 and PEDF by ELISA. Inhibitors of STAT and SMAD signal transduction pathways were used to validate the effects of IFN-γ and TGF-β. Conventional and Real time PCR techniques were used for the gene expression studies.
IFN-γ, TNF-α and IL-1 significantly increased secretion of VEGF-C by both HCE and HCRF cells. TNF-α, IL-1 and TGF-β enhanced secretion of VEGF-A by HCRF but not HCE. IFN-γ down regulated VEGF-A secretion induced by TNF-α, IL-1 (407 pg/ml Vs 60 pg/ml) and TGF-β (485 pg/ml Vs 205 pg/ml). IFN-γ and TGF-β enhanced secretion of sVEGF-R1 (sFlt) by HCRF significantly. JAK-1 and TGF-βR1 inhibitors reversed the effects of IFN-γ and TGF-β respectively indicating the specificity of the actions of these agents. VEGF-D, Angiogenin were not secreted by HCE and HCRF under any of the above conditions. High levels of PEDF secreted (> 2000 pg/ml) constitutively by HCRF was unaffected by IFN-γ, TNF-α, IL-1 and TGF-β alone or together.
We evaluated the role of inflammatory cytokines and TGF-β in the regulation of the expression of angiogenic factors in corneal resident cells. IFN-γ, TNF-α and IL-1 stimulate VEGF-C secretion suggesting their possible role in lymphangiogenesis. In contrast, down regulation of VEGF-A and upregulation of sVEGF-R1 by IFN-γ indicate that IFN-γ may be a negative regulator of hemangiogenesis in the cornea.
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