Signal transduction controls heterogeneous NF-κB dynamics and target gene expression through cytokine-specific refractory states.
Antony AdamsonChristopher BoddingtonPolly DowntonWilliam RoweJames BagnallConnie LamApolinar Maya-MendozaLorraine SchmidtClaire V HarperDavid G SpillerDavid A RandDean A JacksonMichael R H WhitePawel PaszekPublished in: Nature communications (2016)
Cells respond dynamically to pulsatile cytokine stimulation. Here we report that single, or well-spaced pulses of TNFα (>100 min apart) give a high probability of NF-κB activation. However, fewer cells respond to shorter pulse intervals (<100 min) suggesting a heterogeneous refractory state. This refractory state is established in the signal transduction network downstream of TNFR and upstream of IKK, and depends on the level of the NF-κB system negative feedback protein A20. If a second pulse within the refractory phase is IL-1β instead of TNFα, all of the cells respond. This suggests a mechanism by which two cytokines can synergistically activate an inflammatory response. Gene expression analyses show strong correlation between the cellular dynamic response and NF-κB-dependent target gene activation. These data suggest that refractory states in the NF-κB system constitute an inherent design motif of the inflammatory response and we suggest that this may avoid harmful homogenous cellular activation.
Keyphrases
- lps induced
- inflammatory response
- signaling pathway
- induced apoptosis
- gene expression
- pi k akt
- cell cycle arrest
- oxidative stress
- nuclear factor
- dna methylation
- lipopolysaccharide induced
- blood pressure
- endoplasmic reticulum stress
- copy number
- immune response
- electronic health record
- cell death
- cell proliferation
- big data
- protein protein
- genome wide analysis