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C. N. Nagineni, V. K. Kommineni, A. William, B. Detrick, J. J. Hooks; Expression of Angiogenic Factors by Human Retinal Pigment Epithelial and Choroidal Fibroblast Cells: Inflammatory Cytokines Enhance VEGF-A and VEGF-C Expression. Invest. Ophthalmol. Vis. Sci. 2009;50(13):1184.
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Inflammatory processes have been shown to play a critical role in retinal and choroidal neovascularization disorders such as AMD. We evaluated the effects of cytokines on the expression of angiogenic regulators by retinal cells in order to understand the association between inflammation and AMD.
Primary cultures of human retinal pigment epithelial cells (HRPE) and choroidal fibroblast cells (HCHF) derived from donor eyes were used. Confluent cultures were treated with various cytokines in serum free medium for 24 h. Culture supernatants were used for the analysis of secreted angiogenic factors by ELISA. Gene expression analysis was performed by PCR techniques. Inhibitors of signal transduction pathways were used to validate the effects of the cytokines.
HRPE and HCHF cells constitutively secreted both VEGF-A and VEGF-C. IFN-gamma + TNF-alpha + IL-1 significantly increased secretion (pg/ml) of VEGF-A (control, 20 vs treated, 374) and VEGF-C (control, 151 vs treated, 2413) by HRPE cells. Under these conditions,VEGF-A (95 vs 678) and VEGF-C (66 vs 687) produced by HCHF cells were also significantly enhanced. Angiogenin and sVEGF-R1 secretion by HRPE were significantly enhanced in the presence of all three cytokines. VEGF-D, angiopoietins were not secreted under any of these conditions. High levels of PEDF secreted (> 5000 pg/ml) constitutively by HRPE and HCHF was unaffected by IFN-gamma, TNF-alpha, IL-1 alone or together. Signal transduction inhibitors confirmed the actions of TNF-alpha , IL-1and IFN-gamma.
Constitutive secretion of VEGF-A and VEGF-C by HRPE and HCHF cells suggests a role for VEGF in the maintenance of healthy blood vessels in choroid and retina under normal conditions. In the presence of inflammatory cytokines IFN-gamma, TNF-alpha and IL-1 the secretion of both VEGF-A and VEGF-C by HRPE and HCHF cells were significantly elevated. Therefore, pathological states leading to chronic inflammation would result in VEGF release into the choroid and retina promoting neovascularization processes.
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