Increased Glucocorticoid Receptor Expression and Activity Mediate the LPS Resistance of SPRET/EI Mice

被引:27
作者
Dejager, Lien [2 ]
Pinheiro, Iris [2 ]
Puimege, Leen [2 ]
Fan, Ye-Dong [3 ]
Gremeaux, Lies [4 ]
Vankelecom, Hugo [4 ]
Libert, Claude [1 ,2 ]
机构
[1] VIB, DMBR, B-9052 Ghent, Belgium
[2] Univ Ghent, Dept Biomed Mol Biol, B-9052 Ghent, Belgium
[3] Ghent Univ Hosp, Dept Surg, B-9000 Ghent, Belgium
[4] Katholieke Univ Leuven, Dept Mol Cell Biol, Lab Tissue Plast, B-3000 Louvain, Belgium
关键词
PANCREATIC BETA-CELLS; TUMOR-NECROSIS-FACTOR; HORMONE-RECEPTORS; FEEDBACK-CONTROL; GENE; MECHANISMS; STRESS; LIPOPOLYSACCHARIDE; TRANSCRIPTION; BIOSYNTHESIS;
D O I
10.1074/jbc.M110.154484
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 beta-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.
引用
收藏
页码:31073 / 31086
页数:14
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