Mechanisms of proinflammatory cytokine-induced biphasic NF-κB activation

The transcription factor NF-κB regulates genes involved in innate and adaptive immune response, inflammation, apoptosis, and oncogenesis. Proinflammatory cytokines induce the activation of NF-κB in both transient and persistent phases. We investigated the mechanism for this biphasic NF-κB activation. Our results show that MEKK3 is essential in the regulation of rapid activation of NF-κB, whereas MEKK2 is important in controlling the delayed activation of NF-κB in response to stimulation with the cytokines TNF-α and IL-1α. MEKK3 is involved in the formation of the IκBα:NF-κB/IKK complex, whereas MEKK2 participates in assembling the IκBβ:NF-κB/IKK complex; these two distinct complexes regulate the proinflammatory cytokine-induced biphasic NF-κB activation. Thus, our study reveals a novel mechanism in which different MAP3K and IκB isoforms are involved in specific complex formation with IKK and NF-κB for regulating the biphasic NF-κB activation. These findings provide further insight into the regulation of cytokine-induced specific and temporal gene expression.