| Increased glucocorticoid receptor expression and activity mediate the LPS resistance of SPRET/EI mice. | |
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MedLine Citation:
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PMID: 20663891 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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SPRET/Ei mice are extremely resistant to acute LPS-induced lethal inflammation when compared with C57BL/6. We found that in vivo SPRET/Ei mice exhibit strongly reduced expression levels of cytokines and chemokines. To investigate the role of the potent anti-inflammatory glucocorticoid receptor (GR) in the SPRET/Ei phenotype, mice were treated with the GR antagonist RU486 or bilateral adrenalectomy. Under such conditions, both C57BL/6 and SPRET/Ei mice were strongly sensitized to LPS, and the differences in LPS response between SPRET/Ei and C57BL/6 mice were completely gone. These results underscore the central role of GR in the LPS hyporesponsiveness of SPRET/Ei mice. Compared with C57BL/6, SPRET/Ei mice were found to express higher GR levels, which were reflected in increased GR transactivation. Using a backcross mapping strategy, we demonstrate that the high GR transcription levels are linked to the Nr3c1 (GR) locus on chromosome 18 itself. Unexpectedly, SPRET/Ei mice exhibit a basal overactivation of the hypothalamic-pituitary-adrenal axis, namely strongly increased corticosterone levels, ACTH levels, and adrenocortical size. As a consequence of the excess of circulating glucocorticoids (GCs), levels of hepatic gluconeogenic enzymes are increased, and insulin secretion from pancreatic β-cells is impaired, both of which result in hyperglycemia and glucose intolerance in SPRET/Ei mice. We conclude that SPRET/Ei mice are unique as they display an unusual combination of elevated GR expression and increased endogenous GC levels. Hence, these mice provide a new and powerful tool for the study of GR- and GC-mediated mechanisms, including immune repressive functions, neuroendocrine regulation, insulin secretion, and carbohydrate metabolism. |
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Authors:
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Lien Dejager; Iris Pinheiro; Leen Puimège; Ye-Dong Fan; Lies Gremeaux; Hugo Vankelecom; Claude Libert |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-07-27 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 285 ISSN: 1083-351X ISO Abbreviation: J. Biol. Chem. Publication Date: 2010 Oct |
Date Detail:
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Created Date: 2010-09-27 Completed Date: 2010-10-26 Revised Date: 2012-04-27 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 31073-86 Citation Subset: IM |
Affiliation:
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Department for Molecular Biomedical Research, Flanders Institute for Biotechnology, Ghent University, B9052 Ghent, Belgium. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adrenal Cortex
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metabolism Adrenalectomy Adrenocorticotropic Hormone / metabolism Animals Chromosome Mapping Chromosomes, Mammalian / genetics Corticosterone / metabolism Crosses, Genetic Drug Resistance / drug effects, genetics Gene Expression Regulation / drug effects*, genetics Genetic Loci / genetics Hormone Antagonists / pharmacology Hypothalamo-Hypophyseal System / metabolism Insulin-Secreting Cells / metabolism Lipopolysaccharides / pharmacology* Mice Mifepristone / pharmacology Pituitary-Adrenal System / metabolism Receptors, Glucocorticoid / biosynthesis*, genetics |
| Chemical | |
Reg. No./Substance:
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0/Hormone Antagonists; 0/Lipopolysaccharides; 0/Receptors, Glucocorticoid; 50-22-6/Corticosterone; 84371-65-3/Mifepristone; 9002-60-2/Adrenocorticotropic Hormone |
| Comments/Corrections | |
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