Heat shock response pathways regulate stimulus-specificity and sensitivity of NF-κB signalling to temperature stress

Abstract

Ability to adapt to temperature changes trough the Heat Shock Response (HSR) pathways is one of the most fundamental and clinically relevant cellular response systems. Here we report that Heat Shock (HS) induces a temporally-coordinated and stimulus-specific adaptation of the signalling and gene expression responses of the Nuclear Factor κ B (NF-κB) transcription factor. We show that exposure of MCF7 breast adenocarcinoma cells to 43°C 1h HS inhibits the immediate signalling response to pro-inflammatory Interleukin 1β (IL1β) and Tumour Necrosis Factor α (TNFα) cytokines. Within 4h after HS treatment IL1β-induced responses return to normal levels, but the recovery of the TNFα-induced responses is delayed. Using siRNA knock-down of Heat Shock Factor 1 and mathematical modelling we show that the stimulus-specificity is conferred via the Inhibitory κ B kinase signalosome, with HSR differentially controlling individual cytokine transduction pathways. Finally, using a novel mathematical model we predict and experimentally validate that the HSR cross-talk confers differential cytokine sensitivity of the NF-κB system to a range of physiological and clinically-relevant temperatures. This quantitative understanding of NF-κB and HSR crosstalk mechanisms is fundamentally important for the potential improvement of current hyperthermia protocols.