Vascular Endothelial Growth Factor Exerts Anti-Inflammatory Effects on Human Retinal Pigment Epithelial Cells: A Potential Mechanism for Leukocyte Compartmentalization

Abstract

Abstract: : Purpose: To determine the effect of vascular endothelial growth factor (VEGF) stimulation of cultured human retinal pigment epithelial cells (RPE) on the expression of monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8). Methods: Serum starved human RPE cells (D407) were stimulated with VEGF (0-50 ng/ml). MCP-1 and IL-8 protein and mRNA expression were analyzed by ELISA and real time RT-PCR, respectively. Heme oxygenase-1 (HO-1) inhibitor, and VEGF receptor (VEGFR) VEGFR-1 and VEGFR-2 neutralizing antibodies were used to dissect the mechanisms mediating VEGF-induced effects on MCP-1 and IL-8. Results: VEGF inhibited constitutive and cytokine-induced synthesis and secretion of IL-8 and MCP-1 by human RPE cells through a heme oxygenase-1 (HO-1) dependent mechanism. VEGFR-1 mediated MCP-1 inhibition while IL-8 suppression was relieved by blocking both VEGFR-1 and VEGFR-2. Neutralizing only one receptor abolished IL-8 secretion, suggesting reciprocal negative regulation between VEGFR-1 and VEGFR-2. Conclusions: Our findings provide the framework for assigning a novel uncharacteristic anti-inflammatory role to VEGF, suggesting its tissue-specific activity on chemokine expression facilitating compartmentalization of leukocytes. These findings also are consistent with observed high levels of HO-1 in the RPE of eyes with age-related macular degeneration, a high-VEGF state.

Keywords: retinal pigment epithelium • age-related macular degeneration • inflammation