Heat shock response regulates stimulus-specificity and sensitivity of the pro-inflammatory NF-κB signalling

Abstract

Background 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. Heat Shock (HS) affects the signalling and gene expression responses of the Nuclear Factor κB (NF-κB) transcription factor, a critical regulator of proliferation and inflammation, however, our quantitative understanding of how cells sense and adapt to temperature changes is limited. Methods We used live-cell time-lapse microscopy and mathematical modelling to understand the signalling of the NF-κB system in the human MCF7 breast adenocarcinoma cells in response to pro-inflammatory Interleukin 1β (IL1β) and Tumour Necrosis Factor α (TNFα) cytokines, following exposure to a 37–43 °C range of physiological and clinical temperatures. Results We show that exposure to 43 °C 1 h HS inhibits the immediate NF-κB signalling response to TNFα and IL1β stimulation although uptake of cytokines is not impaired. Within 4 h after HS treatment IL1β-induced NF-κB responses return to normal levels, but the recovery of the TNFα-induced responses is still affected. Using siRNA knock-down of Heat Shock Factor 1 (HSF1) we show that this stimulus-specificity is conferred via the Inhibitory κB kinase (IKK) signalosome where HSF1-dependent feedback regulates TNFα, but not IL1β-mediated IKK recovery post HS. Furthermore, we demonstrate that through the temperature-dependent denaturation and recovery of IKK, TNFα and IL1β-mediated signalling exhibit different temperature sensitivity and adaptation to repeated HS when exposed to a 37–43 °C temperature range. Specifically, IL1β-mediated NF-κB responses are more robust to temperature changes in comparison to those induced by TNFα treatment. Conclusions We demonstrate that the kinetics of the NF-κB system following temperature stress is cytokine specific and exhibit differential adaptation to temperature changes. We propose that this differential temperature sensitivity is mediated via the IKK signalosome, which acts as a bona fide temperature sensor trough the HSR cross-talk. This novel quantitative understanding of NF-κB and HSR interactions is fundamentally important for the potential optimization of therapeutic hyperthermia protocols.

Metal–Organic‐Framework‐Based Hydrogen‐Release Platform for MultieffectiveHelicobacter PyloriTargeting Therapy and Intestinal Flora Protective Capabilities

“…H. pylori ‐mediated inflammation reaction causes inflammatory cells to generate excessive ROS and damages normal gastric epithelial cells. [ 4,22 ] Malondialdehyde (MDA) and superoxide dismutase (SOD) were used to evaluate the capacity of Pd(H) @ ZIF‐8 @ AP to resist oxidative stress, which played an important role in the process of oxidative stress. [ 23 ] Pd(H) @ ZIF‐8 @ AP treatment significantly decreased MDA level, while increasing the level of SOD compared with PBS, indicating the anti‐oxidative stress effect of Pd(H) @ ZIF‐8 @ AP.…”

Ex Vivo Evaluation of Glutamine Treatment in Sepsis and Trauma in a Human Peripheral Blood Mononuclear Cells Model

“…In cells stimulated with cytokine, 193 genes change expression, 86 genes are modulated similarly by cytokine or heat shock, while HS pre-treatment affects the expression of 2/3 of cytokine-modulated genes [ 50 ]. Thus cell exposure to HS (43 °C 1 h) inhibited the NF-κB signaling response to TNF-α and IL-1β stimulation, although uptake of cytokines was not impaired [ 51 ].…”

HSF1 Can Prevent Inflammation following Heat Shock by Inhibiting the Excessive Activation of the ATF3 and JUN&FOS Genes

“…TNFα has both autocrine and paracrine functions that amplify or shape the signaling via NFκB (also stimulating AP1 transcriptional activity [ 52 ] or inducing ATF3 [ 53 ]), thereby promoting an inflammatory response [ 54 ]. It was shown previously that NFκB signaling can not be fully activated by TNFα for several hours after heat shock [ 55 ], and tends to recover faster in cells with normal HSF1 levels compared to cells deficient in HSF1 [ 56 ]. Nevertheless, we observed the highest production of TNFα 6-24 h post-treatment, when NFκB signaling was already restored.…”