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TNF-induced NF-κB 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 IκBα—that define the duration of the first phase of NF-κB 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  iκbα  and  a20 , and identify the latter as a signaling cross-talk mediator controlling inflammatory and developmental responses.

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