Encoding NF-κB temporal control in response to TNF:: distinct roles for the negative regulators IκBα and A20

TNF-induced NF-kappa B activity shows complex temporal regulation whose different phases lead to distinct gene expression programs. Combining experimental studies and mathematical modeling, we identify two temporal amplification steps -one determined by the obligate negative feedback regulator I kappa B alpha-that define the duration of the first phase of NF-kappa B activity. The second phase is defined by A20, whose inducible expression provides for a rheostat function by which other inflammatory stimuli can regulate TNF responses. Our results delineate the nonredundant functions implied by the knockout phenotypes of i kappa b alpha and a20, and identify the latter as a signaling cross-talk mediator controlling inflammatory and developmental responses.