Document Detail


Increased glucocorticoid receptor expression and activity mediate the LPS resistance of SPRET/EI mice.
MedLine Citation:
PMID:  20663891     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Lien Dejager; Iris Pinheiro; Leen Puimège; Ye-Dong Fan; Lies Gremeaux; Hugo Vankelecom; Claude Libert
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-07-27
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  285     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2010 Oct 
Date Detail:
Created Date:  2010-09-27     Completed Date:  2010-10-26     Revised Date:  2012-04-27    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  31073-86     Citation Subset:  IM    
Affiliation:
Department for Molecular Biomedical Research, Flanders Institute for Biotechnology, Ghent University, B9052 Ghent, Belgium.
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MeSH Terms
Descriptor/Qualifier:
Adrenal Cortex / 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:
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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