H 2 S protects lipopolysaccharide-induced inflammation by blocking NFκB transactivation in endothelial cells

• Published in: Toxicology and applied pharmacology 2017-11, Vol.338, p.20
• Main Authors: Bourque, Caitlyn, Zhang, Yanjie, Fu, Ming, Racine, Mélanie, Greasley, Adam, Pei, Yanxi, Wu, Lingyun, Wang, Rui, Yang, Guangdong
• Format: Article
• Language: English
• ISSN: 1096-0333

Hydrogen sulfide (H S) is a novel gasotransmitter and acts as a multifunctional regulator in various cellular functions. Past studies have demonstrated a significant role of H S and its generating enzyme cystathionine gamma-lyase (CSE) in the cardiovascular system. Lipopolysaccharide (LPS), a major pathogenic factor, is known to initiate the inflammatory immune response. The cross talk between LPS-induced inflammation and the CSE/H S system in vascular cells has not yet been elucidated in detail. Here we showed that LPS decreased CSE mRNA and protein expression in human endothelial cells and blocked H S production in mouse aorta tissues. Transfection of the cells with TLR4-specific siRNA knockdown TLR4 mRNA expression and abolished the inhibitory role of LPS on CSE expression. Higher dose of LPS (100μg/ml) decreased cell viability, which was reversed by exogenously applied H S at physiologically relevant concentration (30μM). Lower dose of LPS (10μg/ml) had no effect on cell viability, but significantly induced inflammation gene expressions and cytokines secretion and stimulated cell hyper-permeability. H S treatment prevented LPS-induced inflammation and hyper-permeability. Lower VE-cadherin expression in LPS-incubated cells would contribute to cell hyper-permeability, which was reversed by H S co-incubation. In addition, H S treatment blocked LPS-induced NFκB transactivation. We further validated that LPS-induced hyper-permeability was reversed by CSE overexpression but further deteriorated by CRISPR/Cas9-mediated knockout of CSE. In vivo, deficiency of CSE sensitized the mice to LPS-induced inflammation in vascular tissues. Take together, these data suggest that CSE/H S system protects LPS-induced inflammation and cell hyper-permeability by blocking NFκB transactivation.