Abstract
Compound A possesses glucocorticoid receptor (GR)-dependent anti-inflammatory properties. Just like classical GR ligands, Compound A can repress NF-κB-mediated gene expression. However, the monomeric Compound A-activated GR is unable to trigger glucocorticoid response element-regulated gene expression. The heat shock response potently activates heat shock factor 1 (HSF1), upregulates Hsp70, a known GR chaperone, and also modulates various aspects of inflammation. We found that the selective GR modulator Compound A and heat shock trigger similar cellular effects in A549 lung epithelial cells. With regard to their anti-inflammatory mechanism, heat shock and Compound A are both able to reduce TNF-stimulated IκBα degradation and NF-κB p65 nuclear translocation. We established an interaction between Compound A-activated GR and Hsp70, but remarkably, although the presence of the Hsp70 chaperone as such appears pivotal for the Compound A-mediated inflammatory gene repression, subsequent novel Hsp70 protein synthesis is uncoupled from an observed CpdA-induced Hsp70 mRNA upregulation and hence obsolete in mediating CpdA's anti-inflammatory effect. The lack of a Compound A-induced increase in Hsp70 protein levels in A549 cells is not mediated by a rapid proteasomal degradation of Hsp70 or by a Compound A-induced general block on translation. Similar to heat shock, Compound A can upregulate transcription of Hsp70 genes in various cell lines and BALB/c mice. Interestingly, whereas Compound A-dependent Hsp70 promoter activation is GR-dependent but HSF1-independent, heat shock-induced Hsp70 expression alternatively occurs in a GR-independent and HSF1-dependent manner in A549 lung epithelial cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anti-Inflammatory Agents / chemistry
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Anti-Inflammatory Agents / metabolism
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Anti-Inflammatory Agents / pharmacology
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Cell Line
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DNA-Binding Proteins / metabolism
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Dose-Response Relationship, Drug
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Female
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Gene Expression Regulation* / drug effects
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HSP70 Heat-Shock Proteins / genetics*
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HSP70 Heat-Shock Proteins / metabolism
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HSP90 Heat-Shock Proteins / metabolism
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Heat Shock Transcription Factors
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Humans
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Mice
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Models, Biological
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / metabolism
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Promoter Regions, Genetic*
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Protein Binding
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Receptors, Glucocorticoid / agonists
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Receptors, Glucocorticoid / metabolism*
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Response Elements
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Transcription Factors / metabolism
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Transcriptional Activation*
Substances
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Anti-Inflammatory Agents
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DNA-Binding Proteins
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HSF1 protein, human
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HSP70 Heat-Shock Proteins
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HSP90 Heat-Shock Proteins
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Heat Shock Transcription Factors
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NF-kappa B
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Receptors, Glucocorticoid
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Transcription Factors
Grants and funding
IMB (full) and KDB (in part) are postdoctoral fellows supported by the Research Foundation-Flanders (FWO) (
www.fwo.be). SD holds a Ph. D. fellowship of the Research Foundation-Flanders (FWO) (
www.fwo.be). DC is supported by the Flemish League against Cancer ‘Vlaamse Liga tegen Kanker' (VLK) (
www.tegenkanker.be) and thus the research project was realized with the support of the VLK. NB is sponsored by a Strategic Basic Research (SBO) project of IWT-Vlaanderen (
www.iwt.be). Financial support was provided by 'Geconcerteerde Onderzoeksactiviteiten' (GOA) from UGent (
www.ugent.be) and by Interuniversity Attraction Poles (IAP) [6/18] (
http://www.belspo.be/belspo/iap/index_en.stm). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.