Regulation of VEGFs expression in human retinal cells by cytokines: implications for the role of inflammation in age‐related macular degeneration

Abstract

Chronic inflammation has been proposed to be associated with the pathogenesis of age‐related macular degeneration (AMD). Choroidal neovascularization (CNV) observed in exudative form of AMD results in loss of vision. The objective of this study is to investigate the effects of inflammatory mediators on VEGFs expression in retinal cells. We used human retinal pigment epithelial (HRPE) and choroidal fibroblast cells (HCHF) prepared from adult donor eyes. The effects of inflammatory cytokine (IC) mix (IFN‐γ + TNF‐α + IL‐1β) on global gene expression (Affymetrix GeneChip) profiles in HRPE cells, revealed 10 and 9 fold increase in the expression of VEGF‐A and VEGF‐C respectively. The microarray results were validated by HRPE secretion of VEGFs proteins. IL‐1β is the most potent inducer of VEGFs secretion followed by IFN‐γ and TNF‐α. Combination of any of these cytokines was more effective in enhancing VEGFs secretion in a dose dependent manner. NFκB and JAK‐STAT pathway, but not HIF‐1α, Sp‐1, Sp‐3 and STAT‐3, transcription factors were involved in IC action. VEGFs secretion by HCHF cells was also significantly enhanced by IC. Our results show that three pro‐inflammatory cytokines induce the secretion of VEGFs by HRPE and HCHF cells. These findings indicate that in AMD the presence of pro‐inflammatory cytokines in chronic inflammation promote choroidal and retinal neovascularization.