Interleukin -6 modulates changes in non-rapid eye movements sleep and body temperature after sleep deprivation and immune challenge.

Abstract

Disorders of excessive daytime sleepiness are associated with increased levels of interleukin (IL)-6. It has been proposed that IL-6 plays a significant role in mediating the sleepiness and fatigue of these disorders. Indirect evidence suggests that IL-6 may play a role in the regulation of sleep, but little has been done to directly test this hypothesis. The experiments described in this dissertation utilize IL-6 knockout (KO) mice to determine whether IL-6 is involved in the regulation of sleep and body temperature under basal conditions, in response to sleep deprivation, or in response to immune challenge. IL-6 KO mice and C57BL/6J control mice were surgically implanted with telemeters in the peritoneum to measure core body temperature and the electroencephalogram (EEG). There was no apparent difference between the strains in the percentage of time spent in non-rapid eye movements sleep (NREMS) under basal conditions. However, across the 24-h recording period, IL-6 KO mice spent 30% more time in REMS than did C57BL/6J mice. Both strains of mice responded to 6-h sleep deprivation with equivalent increases in the total amount of NREMS and REMS. However, it took IL-6 KO mice 6 h longer to obtain this additional amount of NREMS. The magnitude of the increase in NREMS delta power after sleep deprivation was similar in both strains. Intraperitoneal (IP) injection of 10 mug lipopolysaccharide (LPS), a highly antigenic bacterial cell wall component, produced identical REMS suppression in both strains, but NREMS increases of IL-6 KO mice were delayed compared to those of C57BL/6J mice. LPS induced slight hypothermia followed by fever when administered at dark onset to C57BL/6J mice, and only fever when given at light onset. In contrast, IL-6 KO mice responded to LPS with profound hypothermia regardless of the timing of administration. Central antagonism of tumor necrosis factor (TNF) attenuated LPS-induced hypothermia, but did not affect the NREMS or REMS responses of either strain. We conclude that IL-6 affects the timing of increases in NREMS after sleep deprivation or immune challenge, may tonically inhibit REMS under basal conditions, and limits hypothermic responses to LPS by inhibiting the central actions of TNF.