IMPAIRMENT OF THE MITOCHONDRIAL ELECTRON CHAIN TRANSPORT PREVENTS NF-KAPPA-B ACTIVATION BY HYDROGEN-PEROXIDE

A large body of work has been devoted to mechanisms leading to the act ivation of the transcription factor NF-kappa B in various cell types. Several studies have indicated that NF-kappa B activation by numerous stimuli depends on the intracellular generation of reactive oxygen spe cies (ROS). In this report, we first demonstrated that inhibition of t he electron transport chain by either rotenone or antimycine A gave ri se to dose-dependent inhibition of NF-kappa B translocation induced by 150 mu M of hydrogen peroxide (H2O2). Conversely, the impairment of t he mitochondrial respiratory chain did not affect T lymphocyte treatme nt by TNF-alpha (tumor necrosis factor alpha) or pre-B lymphocyte trea tment with LPS (lipopolysaccharide). We also showed that oligomycine w hich inhibits ATP synthase and FCCP, which uncouples respiration also led to dose-dependent inhibition of NF-kappa B activation by H2O2. All these inhibitors were also shown to inhibit mitochondrial respiration in lymphocytes assessed by oxygen comsuption. Although only a transie nt drop in ATP concentration was observed when lymphocytes were treate d by H2O2, this effect was remarkably reinforced in the presence of ol igomycine demonstrating the crucial role of ATP in the signal transduc tion pathway induced by H2O2. (C) 1998 Elsevier Science Inc.