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- Title
De-repression of heat shock factor-1 in interleukin-6 treated hepatocytes is mediated by down-regulation of glycogen synthase kinase 3B and MAPK/ERK-1.
- Authors
Wigmore, S.J.; Sangster, K.; Ross, J.A.; McNally, S.J.; Garden, O.J.
- Abstract
Aims: Heat shock proteins (HSP) are cytoprotective and upregulation of these chaperons may reduce ischaemia-reperfusion injury in transplanted organs. HSP induction requires activation of heat shock transcription factor-1 (HSF-1) and we hypothesized that IL-6 would prime the HSP response by causing de-repression of HSF1 resulting in augmented HSP expression in stressed cells. Methods: Huh-7 human hepatocytes were exposed to IL-6 1 ng/ml at 37°C and/or treated with HS at 43°C for 45 min with recovery at normothermia. Following SDS-PAGE, Western blots were performed for active (pAbTEpY) and total MAP kinase pERK, glycogen synthase kinase 3b (GSK3B), and HSP70. GSK3B activity was measured by kinase assay. DNA binding was studied by EMSA and transcriptional activity by transient transfection of a plasmid containing the inducible HSP70 promoter coupled to β-galactosidase. Results: IL-6 treatment decreased active MAPK/pERK and GSK3B expression and GSK3B 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. HSP70 transcription (P < 0·05) and expression (P >< 0·01) was significantly increased in cells treated with IL-6 and subsequently exposed to heat shock, but not in cells exposed to IL-6 at 37°C. Conclusions: IL-6, via inhibition of the repressive kinases MAPK/pERK and GSK3B, converts inactive HSF1 to an intermediate DNA-binding form augmenting transcriptional activation in the presence of a second stressor. This priming mechanism may provide a way of facilitating pre-conditioning strategies for use in transplantation.
- Subjects
HEAT shock proteins; TRANSCRIPTION factors; TRANSPLANTATION of organs, tissues, etc.; ISCHEMIA; REPERFUSION injury
- Publication
British Journal of Surgery, 2003, Vol 90, p46
- ISSN
0007-1323
- Publication type
Article