Achieving stability of lipopolysaccharide-induced NF-κB activation

The activation dynamics of the transcription factor NF-kappa B exhibit damped oscillatory behavior when cells are stimulated by tumor necrosis factor-alpha (TNF alpha) but stable behavior when stimulated by lipopolysaccharide (LPS). LPS binding to Toll-like receptor 4 (TLR4) causes activation of NF-kappa B that requires two downstream pathways, each of which when isolated exhibits damped oscillatory behavior. Computational modeling of the two TLR4-dependent signaling pathways suggests that one pathway requires a time delay to establish early antiphase activation of NF-kappa B by the two pathways. The MyD88-independent pathway required Inferon regulatory factor 3-dependent expression of TNF alpha to activate NF-kappa B, and the time required for TNF alpha synthesis established the delay.