SEPARATION OF OXIDANT-INITIATED AND REDOX-REGULATED STEPS IN THE NF-KAPPA-B SIGNAL-TRANSDUCTION PATHWAY

Studies presented here show that overall NF-kappa B signal transductio n begins with a parallel series of stimuli-specific pathways through w hich cytokines (tumor necrosis factor alpha), oxidants (hydrogen perox ide and mitomycin C), and phorbol ester (phorbol 12 myristate 13-aceta te) individually initiate signaling. These initial pathways culminate in a common pathway through which all of the stimulating agents ultima tely signal NF-kappa B activation. We distinguish the stimuli-specific pathways by showing that the oxidative stimuli trigger NF-kappa B act ivation in only one of two human T-cell lines (Wurzburg but not Jurkat ), whereas tumor necrosis factor eu and phorbol 12-myristate 13-acetat e readily stimulate in both lines. We propose the common pathway as th e simplest way of accounting for the common requirements and propertie s of the signaling pathway. We include a redox-regulatory mechanism(s) in this common pathway to account for the previously demonstrated red ox regulation of NF-kappa B activation in Jurkat cells (in which oxida nts don't activate NF-kappa B); we put tyrosine phosphorylation in the common pathway by showing that kinase activity (inhibitable by herbim ycin A and tyrphostin 47) is required for NF-kappa B activation by all stimuli tested in both cell lines. Since internal sites of oxidant pr oduction have been shown to play a key role in the cytokine-stimulated activation of NF-kappa B, and since tyrosine kinase and phosphatase a ctivities are known to be altered by oxidants, these findings suggest that intracellular redox status controls NF-kappa B activation by regu lating tyrosine phosphorylation event(s) within the common step of the NF-kappa B signal transduction pathway.