Stimulus Specificity of Gene Expression Programs Determined by Temporal Control of IKK Activity

A small number of mammalian signaling pathways mediate a myriad of distinct physiological responses to diverse cellular stimuli. Temporal control of the signaling module that contains IκB kinase (IKK), its substrate inhibitor of NF-κB (IκB), and the key inflammatory transcription factor NF-κB can allow for selective gene activation. We have demonstrated that different inflammatory stimuli induce distinct IKK profiles, and we examined the underlying molecular mechanisms. Although tumor necrosis factor-α (TNFα)-induced IKK activity was rapidly attenuated by negative feedback, lipopolysaccharide (LPS) signaling and LPS-specific gene expression programs were dependent on a cytokine-mediated positive feedback mechanism. Thus, the distinct biological responses to LPS and TNFα depend on signaling pathway-specific mechanisms that regulate the temporal profile of IKK activity.