Ilse M. BeckZuzanna J. DrebertRuben Hoya-AriasAli A. BaharMichael DevosDorien ClarisseSofie DesmetNadia BougarneBart RuttensValerie GossyeGeertrui DeneckerSam LievensMarc BrackeJan TavernierWim DeclercqKris GevaertWimden Van BergheGuy HaegemanKarolien De BosscherUniversiteit GentMemorial Sloan-Kettering Cancer CenterFlanders Interuniversity Institute for BiotechnologyUniversiteit AntwerpenSyracuse UniversityAmgen Belgium S.A.Mahidol University2018-10-192018-10-192013-07-30PLoS ONE. Vol.8, No.7 (2013)193262032-s2.0-84880763916https://repository.li.mahidol.ac.th/handle/20.500.14594/31002Compound 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. © 2013 Beck et al.Mahidol UniversityAgricultural and Biological SciencesBiochemistry, Genetics and Molecular BiologyArticleSCOPUS10.1371/journal.pone.0069115