Inhibition of heat shock protein (molecular weight 90 kDa) attenuates proinflammatory cytokines and prevents lipopolysaccharide-induced liver injury in mice
Open Access
- 22 November 2011
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Hepatology
- Vol. 55 (5), 1585-1595
- https://doi.org/10.1002/hep.24802
Abstract
Endotoxin‐mediated proinflammatory cytokines play a significant role in the pathogenesis of acute and chronic liver diseases. Heat shock protein 90 (molecular weight, 90 kDa) (hsp90) functions as an important chaperone of lipopolysaccharide (LPS) signaling and is required for the production of proinflammatory cytokines. We hypothesized that inhibition of hsp90 would prevent LPS‐induced liver injury by decreasing proinflammatory cytokines. C57BL/6 mice were injected intraperitoneally with an hsp90 inhibitor, 17‐dimethylamino‐ethylamino‐17‐demethoxygeldanamycin (17‐DMAG), and LPS. Parameters of liver injury, proinflammatory cytokines, and associated mechanisms were studied by in vivo and in vitro experiments. Inhibition of hsp90 by 17‐DMAG prevented LPS‐induced increases in serum alanine aminotransferase activity and significantly reduced serum tumor necrosis factor alpha (TNFα) and interleukin‐6 (IL‐6) protein as well as messenger RNA (mRNA) in liver. Enhanced DNA‐binding activity of heat shock transcription factor 1 (HSF1) and induction of target gene heat shock protein 70 (molecular weight, 70 kDa) confirmed hsp90 inhibition in liver. 17‐DMAG treatment decreased cluster of differentiation 14 mRNA and LPS‐induced nuclear factor kappa light‐chain enhancer of activated B cells (NFκB) DNA binding without affecting Toll‐like receptor 4 mRNA in liver. Mechanistic studies revealed that 17‐DMAG‐mediated inhibition of TNFα showed no effect on LPS‐induced NFκB promoter‐driven reporter activity, but significantly decreased TNFα promoter‐driven reporter activity. Chromatin immunoprecipitation assays showed that 17‐DMAG enhanced HSF1 binding to the TNFα promoter, but not the IL‐6 promoter, suggesting HSF1 mediated direct inhibition of TNFα, but not IL‐6. We show that HSF1 indirectly regulates IL‐6 by the induction of another transcription factor, activating transcription factor 3. Inhibition of HSF1, using small interfering RNA, prevented 17‐DMAG‐mediated down‐regulation of NFκB‐binding activity, TNFα, and IL‐6 induction, supporting a repressive role for HSF1 on proinflammatory cytokine genes during hsp90 inhibition. Conclusion: Hsp90 inhibition in vivo reduces proinflammatory cytokines and prevents LPS‐induced liver injury likely through repressive action of HSF1. Our results suggest a novel application for 17‐DMAG in alleviating LPS‐induced liver injury. (HEPATOLOGY 2011)Keywords
This publication has 58 references indexed in Scilit:
- A Phase I Study of the Heat Shock Protein 90 Inhibitor Alvespimycin (17-DMAG) Given Intravenously to Patients with Advanced Solid TumorsClinical Cancer Research, 2011
- Febrile range temperature represses TNF-α gene expression in LPS-stimulated macrophages by selectively blocking recruitment of Sp1 to the TNF-α promoterCell Stress and Chaperones, 2010
- Febrile-range temperature modifies cytokine gene expression in LPS-stimulated macrophages by differentially modifying NF-κB recruitment to cytokine gene promotersAmerican Journal of Physiology-Cell Physiology, 2010
- CYP2E1 potentiation of LPS and TNFα-induced hepatotoxicity by mechanisms involving enhanced oxidative and nitrosative stress, activation of MAP kinases, and mitochondrial dysfunctionGenes & Nutrition, 2009
- HSF1-mediated BAG3 Expression Attenuates Apoptosis in 4-Hydroxynonenal-treated Colon Cancer Cells via Stabilization of Anti-apoptotic Bcl-2 ProteinsJournal of Biological Chemistry, 2009
- Heat-shock Protein 90 Is Essential for Stabilization of the Hepatitis C Virus Nonstructural Protein NS3Published by Elsevier BV ,2009
- Alcohol exposure regulates heat shock transcription factor binding and heat shock proteins 70 and 90 in monocytes and macrophages: implication for TNF-α regulationJournal of Leukocyte Biology, 2008
- Heat Shock Co-Activates Interleukin-8 TranscriptionAmerican Journal of Respiratory Cell and Molecular Biology, 2008
- Heat Shock Protein 90 Inhibitors Prolong Survival, Attenuate Inflammation, and Reduce Lung Injury in Murine SepsisAmerican Journal of Respiratory and Critical Care Medicine, 2007
- HSF1 is required for extra-embryonic development, postnatal growth and protection during inflammatory responses in miceThe EMBO Journal, 1999