NF-κB levels settle to steady-state unless IκBε is missing (bottom).

Two isoforms of the IκB inhibitor of NF-κB are required to turn oscillation into steady regulation during chronic stimulation, according to Kearns et al. (page 659). The use of two out-of-phase regulators may be a common means to control signaling pathways.

NF-κB activation triggers expression of IκBα, which leads to down-regulation of the signaling pathway and a decrease in IκBα transcription. However, under chronic stimulation the NF-κB signaling pathway becomes reactivated as soon as the amount of IκBα drops below a certain level. Thus, in cells engineered so that IκBα is the only IκB isoform present, NF-κB activity oscillates over many cycles. In unmodified cells, however, NF-κB activity is steady, and computational modeling suggested the existence of an active damping mechanism that limits fluctuation.

Kearns et al. found that IκBε expression was also induced by NF-κB. There was, though, a significant delay in its expression relative to IκBα. Mathematical modeling and cell experiments showed that, with the two regulators out of phase due to IκBε's lag, NF-κB expression was dampened to a steady half-maximal level in chronically stimulated cells after an initial peak.

A recent report showed that two signals that trigger NF-κB activity also induce oscillation individually but lead to an even activity level when combined (Covert et al. 2005 Science. 309:1854-7). Thus, Kearns et al. speculate that this sort of regulatory mechanism may be a way for cells to modulate the level of activity of a signaling pathway, rather than being limited to simple on/off switches.