Melatonin inhibits IL-1β-induced monolayer permeability of human umbilical vein endothelial cells via Rac activation

Abstract

Melatonin is a key factor in the coordination of circadian rhythms and seasonal reproduction. Melatonin and its metabolites directly scavenge free radicals, increase the expression of antioxidant enzymes, and play a role in the anti-inflammatory phase of defense responses. At present, there are no direct data available as to melatonin's possible influence on endothelial cell monolayer permeability, which is a major biological process responsible for vascular diseases. The aim of this study was to investigate the effect of melatonin on IL-1β-induced human umbilical vein endothelial cells (HUVECs) monolayer permeability and then to test the involvement of small GTPase Rac in the melatonin-induced endothelial barrier-protective effects as well as cell contact reorganization. It was found that IL-1β treatment increased the permeability of HUVECs monolayer, disrupted adherens junctions, and down-regulated the expression of VE-cadherin which is the main functional protein of adherens junctions. Melatonin, however, decreased dextran permeability and increased intercellular adherens junction areas reflecting an endothelial cell barrier-protective response. Furthermore, melatonin dramatically improved IL-1β-induced Rac inactivation. Our results show that the barrier-protective effects of melatonin on endothelial cells are mediated by Rac activation and leads to enhancement of adherens junctions.