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PubMed · 15555563

Glucocorticoids decrease the bioavailability of TGF-beta which leads to a reduced TGF-beta signaling in hepatic stellate cells.

Ursula Bolkenius·Daniela Hahn·Axel M Gressner·Katja Breitkopf·Steven Dooley·Lucia Wickert
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Abstract

Glucocorticoids bound to their receptors transmit information, which regulates numerous physiological and pathophysiological responses, amongst others glucose metabolism, wound healing, inflammation, and stress, either directly as transcription factors by binding DNA elements of target genes or indirectly by protein-protein interactions with other transcription factors. TGF-beta, a key factor in activation of hepatic stellate cells (HSC), induces production of extracellular matrix, this being a prerequisite for the development of liver fibrosis. Glucocorticoids and their receptors may provide a crosstalk with the TGF-beta-Smad signaling pathway by antagonizing TGF-beta effects. We studied the influence of glucocorticoids on the TGF-beta isoform and Smad mRNA expression, TGF-beta secretion, and signaling in activated HSC using gene-specific real-time PCR, ELISA, and transfection techniques. Dexamethasone treatment reduces TGF-beta mRNA transcription in a time-dependent manner. Activated HSC produce TGF-beta and secrete it into the cell culture medium. After dexamethasone treatment, TGF-beta secretion into the medium is reduced dose-dependently but restorable by mifepristone. Further, we found that reduced secretion of endogenous TGF-beta is accompanied by a reduced TGF-beta signal. Additionally, reporter gene analysis after adenoviral infection with a recombinant virus encoding a Smad-binding-element showed that TGF-beta-Smad signaling is significantly down-regulated by dexamethasone in primary HSC and CFSC, a HSC related cell line. Our data suggest that glucocorticoids inhibit TGF-beta expression, prevent TGF-beta from efficient secretion, and finally lead to reduced TGF-beta signaling in primary HSC.

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Adrenal Cortex HormonesAnimalsBiological AvailabilityCells, CulturedDNA-Binding ProteinsDexamethasoneDose-Response Relationship, DrugGlucocorticoidsHepatocytesMaleRatsSignal TransductionSmad ProteinsTrans-ActivatorsTransforming Growth Factor betaJournal ArticleResearch Support, Non-U.S. Gov't

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Ursula Bolkenius, Daniela Hahn, Axel M Gressner, Katja Breitkopf, Steven Dooley, Lucia Wickert. 2004-12-24. Glucocorticoids decrease the bioavailability of TGF-beta which leads to a reduced TGF-beta signaling in hepatic stellate cells.. https://doi.org/10.1016/j.bbrc.2004.10.164

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