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

The consequences of glucocorticoid receptor (GR) dysfunction for neuroimmun oendocrine responses to an inflammatory challenge were studied in transgeni c mice expressing antisense RNA directed against the GR [GR-impaired (GR-I) mice]. Mice were implanted intraperitoneally with a biotelemetry transmitt er to monitor body temperature and locomotion, GR-I mice showed decreased l ocomotion and body temperature during the dark phase of the diurnal cycle. Intraperitoneal administration of saline caused a rapid increase in body te mperature in control mice, which was terminated within 90 min, In GR-i mice , however, body temperature remained elevated for about 6 h, Intraperitonea l injection of endotoxin (10 mu g/mouse) produced a biphasic fever in contr ol mice. However, in endotoxin-injected GR-I mice, body temperature was not significantly different from their saline-injected controls during the fir st 6 h. Body temperature then increased and remained elevated during the ni ght 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 augment ed rise in plasma ACTH, but not in corticosterone levels, The endotoxin-ind uced increase in serum levels of interleukin-1 beta and interleukin-6 was n ot different between the strains, However, whereas in control mice tumour n ecrosis 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 phy siological and humoral responses to an acute inflammatory challenge. These findings expand our understanding about the neuroendocrine and physiologica l disturbances associated with stress-related disorders.