Increased glucocorticoid receptor expression and activity mediate the LPS resistance of SPRET/EI mice.
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.
Dejager
Lien
L
Department for Molecular Biomedical Research, Flanders Institute for Biotechnology, Ghent University, B9052 Ghent, Belgium.
Pinheiro
Iris
I
Puimège
Leen
L
Fan
Ye-Dong
YD
Gremeaux
Lies
L
Vankelecom
Hugo
H
Libert
Claude
C
D000302:Adrenal Cortex / Q000378:metabolism; D000315:Adrenalectomy; D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D002874:Chromosome Mapping; D033481:Chromosomes, Mammalian / Q000235:genetics; D003345:Corticosterone / Q000378:metabolism; D003433:Crosses, Genetic; D004351:Drug Resistance / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D056426:Genetic Loci / Q000235:genetics; D006727:Hormone Antagonists / Q000494:pharmacology; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D015735:Mifepristone / Q000494:pharmacology; D010913:Pituitary-Adrenal System / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000096:biosynthesis* / Q000235:genetics
D006727:Hormone Antagonists; D008070:Lipopolysaccharides; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; D000324:Adrenocorticotropic Hormone; D003345:Corticosterone