Transcription factors as activators of gene transcription: AP-1 and NF-kappa B.

Cells respond to a range of cytokines and other inflammatory stimuli by selectively expressing a wide range of genes. These proinflammatory signals bind to receptors and initiate intracellular signalling cascades. This results in the activation of proinflammatory deoxyribonucleic acid (DNA)-binding proteins or transcription factors such as activator protein-1 (AP-1) or nuclear factor-kappa B (NF-kappa B). Following activation, these factors bind to specific recognition sequences in the control regions (promoters) of target genes causing modulation of gene transcription. Furthermore, numerous sites for regulation of cytokine and cytokine receptor genes by these transcription factors are found in their promoter regions. Many factors affect the formation and activity of AP-1 dimers (Fos and Jun heterodimers) through protein specific interactions or by the modulation of pre-existing complexes by phosphorylation. These complexes can vary markedly in their ability to stimulate gene transcription. Thus, induction of AP-1 activity is regulated by stimuli that either induce the de novo synthesis of AP-1 subunits or increase the activity of previously formed AP-1 dimers. NF-kappa B is activated by a number of agents including tumour necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), lipopolysaccharide (LPS) and viruses. NF-kappa B plays a central role in a range of immunological responses due to its ability to switch on inflammatory genes which lead to further activation of NF-kappa B is a heterodimer of proteins which vary in their ability to bind to DNA and/or to activate gene transcription. NF-kappa B activation is primarily regulated by sequestration of heterodimers within the cytoplasm as inactive complexes with inhibitory molecules (inhibitory-kappa B (I-kappa B)). Treatment of cells with inducing agents results in the phosphorylation of the I-kappa B molecule which is targeted for rapid degradation. This causes a rapid dissociation of the cytoplasmic NF-kappa B/I-kappa B complexes and allows translocation of the active NF-kappa B to the nucleus. Cross-coupling between NF-kappa B and AP-1 has been described which results in a synergistic increase in activity at both AP-1 and NF-kappa B sites. Elevation of both AP-1 and NF-kappa B, as reported in asthma, may therefore lead to far greater inflammation than would be present if either transcription factor alone were activated.