| Dokumentenart: | Artikel | ||||
|---|---|---|---|---|---|
| Titel eines Journals oder einer Zeitschrift: | European Journal of Gastroenterology & Hepatology | ||||
| Verlag: | LIPPINCOTT WILLIAMS & WILKINS | ||||
| Ort der Veröffentlichung: | PHILADELPHIA | ||||
| Band: | 17 | ||||
| Nummer des Zeitschriftenheftes oder des Kapitels: | 2 | ||||
| Seitenbereich: | S. 169-177 | ||||
| Datum: | 2005 | ||||
| Institutionen: | Medizin > Lehrstuhl für Innere Medizin I | ||||
| Identifikationsnummer: |
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| Stichwörter / Keywords: | PRIMARY BILIARY-CIRRHOSIS; PRIMARY SCLEROSING CHOLANGITIS; PROTEIN-KINASE-C; BILE-ACIDS; TRANSCRIPTIONAL ACTIVATION; TAUROURSODEOXYCHOLIC ACID; DEPENDENT TRANSCRIPTION; CONTROLLED TRIAL; GENE-EXPRESSION; PHOSPHORYLATION; glucocorticoid receptor activation; glucocorticoid responsive element; glucocorticoid receptor binding; ursodeoxycholic acid; immunomodulation | ||||
| Dewey-Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin | ||||
| Status: | Veröffentlicht | ||||
| Begutachtet: | Ja, diese Version wurde begutachtet | ||||
| An der Universität Regensburg entstanden: | Ja | ||||
| Dokumenten-ID: | 70937 |
Web of ScienceZusammenfassung
Background and aims Ursodeoxycholic acid (UDCA), a hydrophilic bile acid, improves biochemical, immunopathological and histological parameters in chronic cholestatic liver diseases. The immunomodulatory properties of UDCA show interesting similarities with the effects of glucocorticoids. We investigated the activation of the glucocorticoid receptor by UDCA and the glucocorticoid receptor ...
Zusammenfassung
Background and aims Ursodeoxycholic acid (UDCA), a hydrophilic bile acid, improves biochemical, immunopathological and histological parameters in chronic cholestatic liver diseases. The immunomodulatory properties of UDCA show interesting similarities with the effects of glucocorticoids. We investigated the activation of the glucocorticoid receptor by UDCA and the glucocorticoid receptor dependent gene expression in primary rat hepatocytes as well as binding of radiolabelled UDCA to the glucocorticoid receptor ligand binding site expressed in a glucocorticoid receptor fusion protein. Methods Primary rat hepatocytes in culture were cotransfected with a luciferase reporter gene construct (GRE-luc) containing a glucocorticoid receptor responsive element (GRE) and a glucocorticoid receptor expression vector (6RGR) followed by stimulation with dexamethasone or UDCA. Luciferase activity was determined and specific binding of glucocorticoid receptor to the GRE was confirmed by an electrophoretic mobility shift assay (EMSA). The glucocorticoid receptor binding site was expressed in a GR-myc fusion protein and binding of radiolabelled UDCA to the fusion protein was determined. Results Incubation of co-transfected hepatocytes with 0.1-1.000 mu M dexamethasone or 0.1-1.000 mu M UDCA led to an 11.9- to 20.85-fold (dexamethasone) and 2.6- to 4.3-fold (UDC) increase of luciferase activity. Mobility shift assays using nuclear extracts from transfected and stimulated hepatocytes also showed a dose dependent increase of DNA binding after stimulation with UDCA. However, incubation of the GR-myc fusion protein with radiolabelled UDCA yielded no specific binding of UDCA to the glucocorticoid receptor binding site, whereas dexamethasone showed specific binding of the fusion protein. Conclusions UDCA activates the intracellular glucocorticoid receptor in a dose-dependent manner. Direct binding of the glucocorticoid receptor by radiolabelled UDCA at the glucocorticoid receptor binding site could be excluded as the mechanism of activation. The mechanisms involved in UDCA-mediated glucocorticoid receptor activation and possible targeted glucocorticoid receptor activation due to partial UDCA tissue specificity warrant further elucidation. (c) 2005 Lippincott Williams C Wilkins.
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