科研之友
微信
新浪微博
Facebook
分享链接
摘要
Recent evidence suggested that ClC-3 channel/antiporter is involved in regulation of nuclear factor (NF)-kappa B activation. However, the mechanism explaining how ClC-3 modulates NF-kappa B signaling is not well understood. We hypothesized that ClC-3-dependent alteration of intracellular chloride concentration ([Cl-](i)) underlies the effect of ClC-3 on NF-kappa B activity in endothelial cells. Here, we found that reduction of [Cl-](i) increased tumor necrosis factor-alpha (TNF alpha)-induced expression of intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 and adhesion of monocytes to endothelial cells (P<0.05; n=6). In Cl- reduced solutions, TNF alpha-evoked I kappa B kinase complex beta and inhibitors of kappa B alpha phosphorylation, inhibitors of kappa B alpha degradation, and NF-kappa B nuclear translocation were enhanced. In addition, TNF alpha and interleukin 1 beta could activate an outward rectifying Cl- current in human umbilical vein endothelial cells and mouse aortic endothelial cells. Knockdown or genetic deletion of ClC-3 inhibited or abolished this Cl- conductance. Moreover, Cl- channel blockers, ClC-3 knockdown or knockout remarkably reduced TNF alpha-induced intercellular adhesion molecule 1 and vascular cell adhesion molecule 1expression, monocytes to endothelial cell adhesion, and NF-kappa B activation (P<0.01; n=6). Furthermore, TNF alpha-induced vascular inflammation and neutrophil infiltration into the lung and liver were obviously attenuated in ClC-3 knockout mice (P<0.01; n=7). Our results demonstrated that decrease of [Cl-](i) induced by ClC-3-dependent Cl- efflux promotes NF-kappa B activation and thus potentiates TNF alpha-induced vascular inflammation, suggesting that inhibition of ClC-3-dependent Cl- current or modification of intracellular Cl- content may be a novel therapeutic approach for inflammatory diseases. (Hypertension. 2012;60:1287-1293.)
