Impaired glucocorticoid receptor function evolves in aberrant physiological responses to bacterial endotoxin

A C Linthorst, S Karanth, N Barden, F Holsboer, J M H M Reul

Research output: Contribution to journalArticle (Academic Journal)peer-review

19 Citations (Scopus)


The consequences of glucocorticoid receptor (GR) dysfunction for neuroimmunoendocrine responses to an inflammatory challenge were studied in transgenic mice expressing antisense RNA directed against the GR [GR-impaired (GR-i) mice]. Mice were implanted intraperitoneally with a biotelemetry transmitter to monitor body temperature and locomotion. GR-i mice showed decreased locomotion and body temperature during the dark phase of the diurnal cycle. Intraperitoneal administration of saline caused a rapid increase in body temperature in control mice, which was terminated within 90 min. In GR-i mice, however, body temperature remained elevated for about 6 h. Intraperitoneal injection of endotoxin (10 micrograms/mouse) produced a biphasic fever in control mice. However, in endotoxin-injected GR-i mice, body temperature was not significantly different from their saline-injected controls during the first 6 h. Body temperature then increased and remained elevated during the night period. Both strains showed hypolocomotion after endotoxin. In a second experiment, mice were injected intraperitoneally with saline or endotoxin and killed after 1, 3, 6 or 24 h. In GR-i mice, endotoxin caused an augmented rise in plasma ACTH, but not in corticosterone levels. The endotoxin-induced increase in serum levels of interleukin-1 beta and interleukin-6 was not different between the strains. However, whereas in control mice tumour necrosis factor-alpha levels were below detection at the time points studied, substantial levels of this cytokine were found in the serum of GR-i mice 1 h after endotoxin administration. It may be concluded that life-long impairment of GR evolves in aberrant physiological and humoral responses to an acute inflammatory challenge. These findings expand our understanding about the neuroendocrine and physiological disturbances associated with stress-related disorders.
Original languageEnglish
Pages (from-to)178-86
Number of pages9
JournalEuropean Journal of Neuroscience
Issue number1
Publication statusPublished - Jan 1999


  • Injections, Intraperitoneal
  • Animals
  • Tumor Necrosis Factor-alpha
  • Transgenes
  • Receptors, Glucocorticoid
  • Mice
  • Antisense Elements (Genetics)
  • Mice, Transgenic
  • Adrenocorticotropic Hormone
  • Behavior, Animal
  • Corticosterone
  • Promoter Regions, Genetic
  • Body Temperature
  • Circadian Rhythm
  • Interleukin-1
  • Locomotion
  • Interleukin-6
  • Lipopolysaccharides
  • Sodium Chloride
  • Neurosecretory Systems
  • Male


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