NF-κB Dynamics Discriminate between TNF Doses in Single Cells.

Area of Science:

• Cellular Biology
• Systems Biology
• Immunology

Background:

• Cytokine-dependent dynamics of nuclear factor κB (NF-κB) are crucial for cell fate decisions.
• The extent to which single cells discriminate cytokine dose remains unclear, with debate on switch-like versus graded responses.

Purpose of the Study:

• To investigate single-cell dose discrimination mechanisms of NF-κB in response to tumor necrosis factor (TNF).
• To determine if NF-κB dynamics encode more information about cytokine dose than a simple switch-like model predicts.

Main Methods:

• Measuring dynamic subcellular localization of NF-κB under various TNF stimulation conditions.
• Applying an information theory framework to analyze signaling dynamics and non-responsive cell populations.

Main Results:

• Single-cell information transmission capacity for TNF dose exceeds predictions from a switch-like model.
• NF-κB dynamics encode information for multiple TNF-dependent cellular states with a variable activation threshold across the population.
• Cells demonstrate graded responses to TNF across several orders of magnitude in concentration.

Conclusions:

• Single-cell NF-κB responses are not strictly switch-like but provide graded information about cytokine dose.
• Cells possess regulatory mechanisms for fine-tuning cytokine responses beyond initial activation.
• Understanding these dynamics is key to deciphering cell fate determination in response to external stimuli.