MUTUAL REGULATION OF THE TRANSCRIPTIONAL ACTIVATOR NF-KAPPA-B AND ITS INHIBITOR, I-KAPPA-B-ALPHA

The NF-kappaB transcription factor complex is sequestered in the cytoplasm by the inhibitory protein IkappaB-alpha (MAD-3). Various cellular stimuli relieve this inhibition by mechanisms largely unknown, leading to NF-kappaB nuclear localization and transactivation of its target genes. It is demonstrated here with human T lymphocytes and monocytes that different stimuli, including tumor necrosis factor alpha and phorbol 12-myristate 13-acetate, cause rapid degradation of IkappaB-alpha, with concomitant activation of NF-kappaB, followed by a dramatic increase in IkappaB-alpha mRNA and protein synthesis. Transfection studies reveal that the IkappaB-alpha mRNA and the encoded protein are potently induced by NF-kappaB and by homodimers of p65 and of c-Rel. We propose a model in which NF-kappaB and IkappaB-alpha mutually regulate each other in a cycle: saturating amounts of the inhibitory IkappaB-alpha protein are destroyed upon stimulation, allowing rapid activation of NF-kappaB. Subsequently, IkappaB-alpha mRNA and protein levels are quickly induced by the activated NF-kappaB. This resurgence of IkappaB-alpha protein acts to restore an equilibrium in which NF-kappaB is again inhibited.