Achieving Stability of Lipopolysaccharide-Induced NF-κB Activation

作者：Markus W. Covert, Thomas Leung, Jahlionais E. Gaston, David Baltimore · 发表于：Science · 年份：2005 · DOI：10.1126/science.1112304 · 被引用次数：610 · 研究领域：NF-κB Signaling Pathways、Immune Response and Inflammation、Natural product bioactivities and synthesis

The activation dynamics of the transcription factor NF-kappaB exhibit damped oscillatory behavior when cells are stimulated by tumor necrosis factor-alpha (TNFalpha) but stable behavior when stimulated by lipopolysaccharide (LPS). LPS binding to Toll-like receptor 4 (TLR4) causes activation of NF-kappaB 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 anti-phase activation of NF-kappaB by the two pathways. The MyD88-independent pathway required Inferon regulatory factor 3-dependent expression of TNFalpha to activate NF-kappaB, and the time required for TNFalpha synthesis established the delay.