title: De-repression of heat shock transcription factor-1 in interleukin-6- treated hepatocytes is mediated by downregulation of glycogen synthase kinase 3beta and MAPK/ERK-1.
abstract: Expression of inducible heat shock protein (HSP70) requires activation of heat shock transcription factor-1 (HSF-1). Recent evidence suggests that interleukin-6 (IL-6) can modify the response of HSF-1 to heat. We hypothesized that IL-6 would prime the HSP response by causing de-repression of HSF-1 resulting in augmented HSP expression in stressed cells. In this study we show that IL-6 has no direct effect on HSP70 expression at 37 degrees C but does augment HSP70 expression in response to heat. IL-6 treatment decreased active MAPK/pERK and glycogen synthase kinase 3beta (GSK3beta) expression and GSK3beta kinase activity. In IL-6-treated cells, monomeric HSF-1 accumulated in the cytoplasm and nucleus, bound DNA but was transcriptionally inactive. On exposure to heat shock this modified monomer assumed the transcriptionally active phenotype with trimerization and hyperphosphorylation evident. The increased induction of HSP70 in IL-6 and heat-treated cells was inhibited using PI3-kinase inhibitors or Akt inhibition and was HSF-1 dependent. IL-6, via the PI3-kinase/Akt pathway leads to inhibition of the repressive kinases MAPK/pERK and GSK3beta, and this converts inactive HSF-1 to an intermediate DNA-binding form augmenting transcriptional activation in the presence of a second stressor.
authors.affiliation: Tissue Injury and Repair Group, MRC Centre for Inflammation Research, Medical School 6th Floor, Edinburgh EH8 9AG, UK. s.wigmore@bham.ac.uk
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Wigmore
authors.forename: Kathryn
authors.initials: K
authors.lastname: Sangster
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: McNally
authors.forename: Ewen M
authors.initials: EM
authors.lastname: Harrison
authors.forename: James A
authors.initials: JA
authors.lastname: Ross
authors.forename: Kenneth C H
authors.initials: KC
authors.lastname: Fearon
authors.forename: O James
authors.initials: OJ
authors.lastname: Garden
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D002467:Cell Nucleus / Q000187:drug effects; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D003593:Cytoplasm / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D000076249:Heat Shock Transcription Factors; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D006801:Humans; D006979:Hyperthermia, Induced; D015850:Interleukin-6 / Q000494:pharmacology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D020033:Protein Isoforms / Q000378:metabolism; D020836:Protein Structure, Quaternary / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D002867:Chromones; D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D018840:HSP70 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D015850:Interleukin-6; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms; D012333:RNA, Messenger; D014157:Transcription Factors; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D048052:Mitogen-Activated Protein Kinase 3; D038362:Glycogen Synthase Kinase 3; D000077191:Wortmannin