De-repression of heat shock transcription factor-1 in interleukin-6- treated hepatocytes is mediated by downregulation of glycogen synthase kinase 3β and MAPK/ERK-1
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°C but does augment HSP70 expression in response to heat. IL-6 treatment decreased active MAPK/pERK and glycogen synthase kinase 3β (GSK3β) expression and GSK3β 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 GSK3β, and this converts inactive HSF-1 to an intermediate DNA-binding form augmenting transcriptional activation in the presence of a second stressor.
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Document Type: Research Article
Affiliations: Tissue Injury and Repair Group, MRC Centre for Inflammation Research, Medical School 6th Floor, Edinburgh EH8 9AG, UK., Email: [email protected]
Publication date: March 1, 2007
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- The International Journal of Molecular Medicine is a monthly, peer-reviewed journal devoted to the publication of high quality studies related to the molecular mechanisms of human disease. The journal welcomes research on all aspects of molecular and clinical research, ranging from biochemistry to immunology, pathology, genetics, human genomics, microbiology, molecular pathogenesis, molecular cardiology, molecular surgery and molecular psychology.
The International Journal of Molecular Medicine aims to provide an insight for researchers within the community in regard to developing molecular tools and identifying molecular targets for the diagnosis and treatment of a diverse number of human diseases.
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