Intracellular redox state regulates activation of nuclear factor .KAPPA.B and expression of the genes for adhesion molecule in human pulmonary artery endothelial cells.
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Transcription factor nuclear factor κB (NF-κB) controls gene expression of a number of genes including endothelial cell adhesion molecules such as E-selection and ICAM-1. These cell adhesion molecules are known to play important roles in a critical step of acute lung injury. We tested the hypothesis that TNFα-induced ICAM-1 and E-selectin gene expression requires perturbation of cellular redox equilibrium, and the subsequent activation of redox sensitive transcription factor NF-κB that binds to its cognate promoter sequences leading to increased transcription of ICAM-1 and E-selectin genes in pulmonary artery endothelial cells. Stimulation of human pulmonary artery endothelial (HPAE) cells with TNFα (100 U/ml) decreased intracellular glutathione (GSH) content (-80%) with a concomitant increase in oxidized GSH (GSSG), activated NF-κB, and enhanced the transcription of ICAM-1 and E-selectin genes. Pretreatment with N-acetyl-L-cysteine (NAC), an antioxidant and precursor for GSH synthesis, for 0.5 h prevented the decrease in GSH content, inhibited the activation of NF-κB, and the lack of activated NF-κB prevented the activation of the ICAM-1 and E-selectin promoters and thereby the transcription of these genes. These results indicate the involvement of oxidant-dependent NF-κB activation in this pathway and the feasibility of using antioxidant or anti-NF-κB reagents in preventing acute lung injury associated with TNFα release.
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