Abstract
In tissues and tumours, cell behaviours are regulated by multiple time-varying signals. While in the laboratory cells are often exposed to a stimulus for the duration of the experiment, in vivo exposures may be much shorter. In this study, we monitored NF-κB and caspase signalling in human cancer cells treated with a short pulse of Tumour Necrosis Factor (TNF). TNF is an inflammatory cytokine that can induce both the pro-survival NF-κB-driven gene transcription pathway and the pro-apoptotic caspase pathway. We find that a few seconds of exposure to TNF is sufficient to activate the NF-κB pathway in HeLa cells and induce apoptotic cell death in both HeLa and Kym-1 cells. Strikingly, a 1-min pulse of TNF can be more effective at killing than a 1-hour pulse, indicating that in addition to TNF concentration, duration of exposure also coordinates cell fate decisions.
Highlights
NF-κB signalling and cell fate decisions in response to a short pulse of tumour necrosis factor
Using a simple microfluidic system, we characterized the cellular responses to different durations of exposure to Tumour necrosis factor (TNF) in single-cells
Our results demonstrate that the minimum pulse required for TNF-induced signal transduction is concentration-dependent, and that at high TNF concentrations, a pulse as short as 10–30 sec can induce significant NF-κB translocation and a pulse of sec or 1 min can induce caspase activation and apoptosis
Summary
NF-κB signalling and cell fate decisions in response to a short pulse of tumour necrosis factor. Cell behaviours are regulated by multiple time-varying signals. Many experiments characterize cellular responses to continuous exposure to a stimulus, stimuli in normal tissues and tumours are often time-varying. One such stimulus is Tumour necrosis factor (TNF). TNF regulates diverse cellular behaviours such as migration, differentiation and apoptosis[5,6,7,8] This diversity of responses may stem from the fact that TNF initiates a paradoxical network of pro-survival and pro-apoptotic intracellular signals.
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