|The nuclear transcription factor NF-kB is important
in the expression of many genes whose proteins are involved in the control of apoptosis
(cell suicide), in the development of B and T cells, in anti-viral and bacterial
responses, in responses to multiple stresses, in embryonic development and in inflammatory
Downstream products of NF-kB activation include inflammatory cytokines (messenger molecules) important for leukocyte activation and leukocyte recruitment, tumor necrosis factor (TNF), nitric oxide synthase (NOS), and hence regulation of vascular tone, cell adhesion molecule expression involved in inflammatory responses, and viral activation such as in HIV.
Ultraviolet radiation, cigarette smoke, ozone and many other stimuli activate NF-kB. This appears to be mediated through the production of reactive oxygen species (ROS). NF-kB exists in the cytosol as a pre-formed trimeric complex. The P50/P65 protein dimer is associated with an inhibitory protein known as I-kB. Oxidants trigger a change in the cell that results in phosphorylation of the I-kB subunit. After I-kB is phosphorylated, a process of the proteolytic digestion of this subunit is activated. When the inhibitor subunit is dislodged from the P60/P65 heterodimer the activator NF-kB can migrate to the nucleus and bind to DNA, thereby initiating transcription.
Reduced thioredoxin is an essential component contributing to the reduction of activated NF-kB allowing it to bind to DNA. There are many redox-sensitive steps in the signal transduction pathways.Oxidants can be counteracted by antioxidants that modulate NF-kB activation. Among the antioxidants that have been demonstrated to be effective are vitamin E and dihydrolipoic acid. The following scheme briefly summarizes oxidant-induced activation of NF-kB signal transduction.