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)

19 Citations (Scopus)

Abstract

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
Volume11
Issue number1
Publication statusPublished - Jan 1999

Keywords

  • 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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