Achieving stability of lipopolysaccharide-induced NF-kappaB activation.
|Title||Achieving stability of lipopolysaccharide-induced NF-kappaB activation.|
|Publication Type||Journal Article|
|Year of Publication||2005|
|Authors||Covert MW, Leung TH, Gaston JE, Baltimore D|
|Date Published||2005 Sep 16|
|Keywords||Adaptor Proteins, Signal Transducing, Adaptor Proteins, Vesicular Transport, Animals, Antigens, Differentiation, Cell Line, Cells, Cultured, Computer Simulation, Cycloheximide, DNA-Binding Proteins, Gene Expression Profiling, Gene Expression Regulation, I-kappa B Kinase, I-kappa B Proteins, Interferon Regulatory Factor-3, Kinetics, Lipopolysaccharides, Mice, Models, Biological, Myeloid Differentiation Factor 88, NF-kappa B, Oligonucleotide Array Sequence Analysis, Protein Synthesis Inhibitors, Protein-Serine-Threonine Kinases, Receptors, Immunologic, Signal Transduction, Time Factors, Toll-Like Receptor 4, Transcription Factors, Tumor Necrosis Factor-alpha|
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.