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 I kappa B kinase (IKK), its substrate inhibitor of NF-kappa B (I kappa B), and the key inflammatory transcription factor NF-kappa B 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-alpha (TNF alpha)-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 TNF alpha depend on signaling pathway-specific mechanisms that regulate the temporal profile of IKK activity.