Cross talk between cytokine and hyperthermia-induced pathways: identification of different subsets of NF-κB-dependent genes regulated by TNFα and heat shock

Abstract

Heat shock inhibits NF-κB signaling, yet the knowledge about its influence on the regulation of NF-κB-dependent genes is limited. Using genomic approaches, i.e., expression microarrays and ChIP-Seq, we aimed to establish a global picture for heat shock-mediated impact on the expression of genes regulated by TNFα cytokine. We found that 193 genes changed expression in human U-2 osteosarcoma cells stimulated with cytokine (including 77 genes with the κB motif in the proximal promoters). A large overlap between sets of genes modulated by cytokine or by heat shock was revealed (86 genes were similarly affected by both stimuli). Binding sites for heat shock-induced HSF1 were detected in regulatory regions of 1/3 of these genes. Furthermore, pre-treatment with heat shock affected the expression of 2/3 of cytokine-modulated genes. In the largest subset of co-affected genes, heat shock suppressed the cytokine-mediated activation (antagonistic effect, 83 genes), which genes were associated with the canonical functions of NF-κB signaling. However, subsets of co-activated and co-repressed genes were also revealed. Importantly, pre-treatment with heat shock resulted in the suppression of NF-κB binding in the promoters of the cytokine-upregulated genes, either antagonized or co-activated by both stimuli. In conclusion, we confirmed that heat shock inhibited activation of genes involved in the classical cytokine-mediated functions of NF-κB. On the other hand, genes involved in transcription regulation were over-represented in the subset of genes upregulated by both stimuli. This suggests the replacement of NF-κB-mediated regulation by heat shock-mediated regulation in the latter subset of genes, which may contribute to the robust response of cells to both stress conditions.Electronic supplementary materialThe online version of this article (doi:10.1007/s00438-015-1055-1) contains supplementary material, which is available to authorized users.

Irradiation withUV‐C inhibitsTNF‐α‐dependent activation of theNF‐κB pathway in a mechanism potentially mediated by reactive oxygen species

“…There were several reports that the heat shock‐induced HSR resulted in the suppression of the TNF‐α‐activated NF‐κB pathway (Knowlton ; Janus et al . , ). Thus, we assessed whether HSR was induced in the HCT116 cells irradiated with UV‐C.…”

“…Among the key stress-induced pathways, there is the so-called heat shock response (HSR), which depends on the activation and accumulation of the heat shock proteins (HSPs) in proteotoxic conditions. There were several reports that the heat shock-induced HSR resulted in the suppression of the TNF-a-activated NF-jB pathway (Knowlton 2006;Janus et al 2011Janus et al , 2015. Thus, we assessed whether HSR was induced in the HCT116 cells irradiated with UV-C.…”

“…Moreover, interference between TNF‐α‐activated NF‐κB and other stress‐triggered pathways, including response to DNA damage, depends on the specific temporal context (Nakajima & Kitamura ; Janus et al . ). TNF‐α‐mediated pre‐activation of NF‐κB may protect cells against UV‐induced apoptosis (Szołtysek et al .…”

“…NF-jB participates in a complex gene transcription network, and its activity is affected by other stress-related transcription factors such as p53, AP-1, NRF2 or HSF1 (Liu et al 2008a,b;Stice & Knowlton 2008;Chaturvedi et al 2011;Gudkov et al 2011;Oeckinghaus et al 2011;Hoesel & Schmid 2013). Moreover, interference between TNF-aactivated NF-jB and other stress-triggered pathways, including response to DNA damage, depends on the specific temporal context (Nakajima & Kitamura 2013;Janus et al 2015). TNF-a-mediated pre-activation of NF-jB may protect cells against UV-induced apoptosis (Szołtysek et al 2008).…”

HSF1 mediated TNF‐α production during proteotoxic stress response pioneers proinflammatory signal in human cells

“…Monocyte or macrophages, however, have been shown to respond to stress in a unique manner (68). Interestingly, gene expression data with U2OS cells did not reveal TNF-a expression during HS (69). Tissue-and context-specific expression of the TNF-a gene can possibly be explained by its absolute requirement for LEF1 ( Fig.…”