title: Impaired glucocorticoid receptor function evolves in aberrant physiological responses to bacterial endotoxin.
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.
authors.affiliation: Max Planck Institute of Psychiatry, Section Neuropsychopharmacology, Munich, Germany.
authors.forename: A C
authors.initials: AC
authors.lastname: Linthorst
authors.forename: S
authors.initials: S
authors.lastname: Karanth
authors.forename: N
authors.initials: N
authors.lastname: Barden
authors.forename: F
authors.initials: F
authors.lastname: Holsboer
authors.forename: M H
authors.initials: MH
authors.lastname: Reul
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D016375:Antisense Elements (Genetics); D001522:Behavior, Animal / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D002940:Circadian Rhythm / Q000502:physiology; D003345:Corticosterone / Q000097:blood; D007274:Injections, Intraperitoneal; D007375:Interleukin-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009490:Neurosecretory Systems / Q000737:chemistry* / Q000187:drug effects / Q000503:physiopathology*; D011401:Promoter Regions, Genetic / Q000502:physiology; D011965:Receptors, Glucocorticoid / Q000235:genetics* / Q000378:metabolism*; D012965:Sodium Chloride / Q000494:pharmacology; D019076:Transgenes / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism