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

Abstract

Heat Shock Factor 1 (HSF1), a transcription factor frequently overexpressed in cancer, is activated by proteotoxic agents and participates in the regulation of cellular stress response. To investigate how HSF1 level affects the response to proteotoxic stress, we integrated data from functional genomics analyses performed in MCF7 breast adenocarcinoma cells. Although the general transcriptional response to heat shock was impaired due to HSF1 deficiency (mainly chaperone expression was inhibited), a set of genes was identified, including ATF3 and certain FOS and JUN family members, whose stress-induced activation was stronger and persisted longer than in cells with normal HSF1 levels. These genes were direct HSF1 targets, suggesting a dual (activatory/suppressory) role for HSF1. Moreover, we found that heat shock-induced inflammatory response could be stronger in HSF1-deficient cells. Analyses of The Cancer Genome Atlas data indicated that higher ATF3, FOS, and FOSB expression levels correlated with low HSF1 levels in estrogen receptor-positive breast cancer, reflecting higher heat shock-induced expression of these genes in HSF1-deficient MCF7 cells observed in vitro. However, differences between the analyzed cancer types were noted in the regulation of HSF1-dependent genes, indicating the presence of cell-type-specific mechanisms. Nevertheless, our data indicate the existence of the heat shock-induced network of transcription factors (associated with the activation of TNFα signaling) which includes HSF1. Independent of its chaperone-mediated cytoprotective function, HSF1 may be involved in the regulation of this network but prevents its overactivation in some cells during stress.

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

“…We chose the 10 mM L-Ala-Gln dose because (a) it corresponds to 10 mM plasma concentration at the recommended infusion rate of 0.75 g/kg L-Ala-Gln [ 40 ], and (b) at this dose, it induces maximal HSP expression, attenuating cytokine release [ 41 ]. In experimental studies, increasing glutamine dose from 2 to 10 mM decreased chemokines in human epithelial cell lines [ 3 ] and reduced the intestinal inflammatory response during cytokine stimulation [ 2 ]. Having accomplished the described HS, LPS, and glutamine interventions, cells were incubated for 4 h at 37 °C and harvested for intracellular staining and flow cytometric HSP90α analysis.…”

“…Multiple organ system failures and increased mortality rates are associated with septic shock [ 2 ]. In sepsis and systemic inflammatory response syndrome (SIRS), a rapid-onset cytokine storm leads to a rapid release of pro-inflammatory mediators and an excessive release of anti-inflammatory cytokines [ 3 ]. Trauma-related SIRS represents another leading cause of morbidity and mortality.…”

“…Immune cells such as lymphocytes and macrophages release pro-inflammatory biomolecules such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1, IL-6, and IL-8 followed by the production of anti-inflammatory mediators such as IL-10, IL-13, or transforming growth factor-β (TGF- β) [ 3 ]. By responding to the cytokine-storm, core temperature rises above a threshold set by the hypothalamus, causing cellular damage and death [ 4 ].…”

“…Although large clinical trials on targeted temperature management have not shown benefits in sepsis, national guidelines recommend normothermia in patients with trauma [ 5 ]. In a large adult cohort, sepsis-related fever was associated with worse outcome [ 6 ], whereas fever control using external cooling to maintain normothermia reduced mortality in septic shock [ 3 ]. Surprisingly, external forced-air warming of normothermic septic patients was associated with lower mortality when compared to afebrile patients [ 7 ].…”

Entamoeba histolytica: In Silico and In Vitro Oligomerization of EhHSTF5 Enhances Its Binding to the HSE of the EhPgp5 Gene Promoter

“…In the context of cardiovascular diseases, they protect the heart from stress damage [21]. HSTFs also play a role in inflammatory diseases [22], such as rheumatoid arthritis [23], affecting their severity and progression.…”