Diurnal variation of lipopolysaccharide-induced alterations in sleep and body temperature of interleukin-6-deficient mice

Abstract

Infectious challenge triggers a broad array of coordinated changes within the host organism, including alterations in sleep-wake behavior and body temperature. Pro-inflammatory cytokines orchestrate many of the behavioral, metabolic, and endocrine responses to immune challenge. Although interleukin (IL)-6 mediates several aspects of sickness behavior, a role for this cytokine as a mediator of alterations in sleep in response to immune challenge has not been established. We evaluated sleep-wake behavior and core body temperature of IL-6-deficient (IL-6 KO; B6.129S6- Il6 tm1Kopf ) mice and C57BL/6J control mice after intraperitoneal (IP) administration of 10 μg lipopolysaccharide (LPS). Because feedback mechanisms that regulate responses to immune challenge exhibit circadian rhythms, we evaluated responses to LPS administered at the beginning of both the light and dark portions of the light:dark cycle. LPS-induced increases in non-rapid eye movements sleep (NREMS) of both mouse strains, but this increase was less pronounced in IL-6 KO mice than in C57BL/6J mice. Strain differences in LPS-induced increases in NREMS were greatest after light-onset administration. During the 12 h light period, NREMS of C57BL/6J mice increased from 53.0 ± 1.7% of recording time after vehicle to 65.4 ± 1.4% of recording time after LPS. During this same time period, NREMS of IL-6 KO mice increased from 50.5 ± 1.8% after vehicle to only 52.4 ± 1.8% of recording time after LPS. REMS of both mouse strains was suppressed to the same extent after LPS, irrespective of timing of administration. LPS-induced fever in C57BL/6J mice, with peak magnitude of 1.4 ± 0.3 °C and 1.8 ± 0.2 °C after dark onset and light onset administration, respectively. In contrast, this dose of LPS-induced profound hypothermia in IL-6 KO mice, with nadirs of hypothermia reaching 4.9 ± 1.0 °C after injection at dark onset and 2.2 ± 0.5 °C after administration at light onset. These results indicate that IL-6 mediates some of the effects of LPS on NREMS and body temperature of mice, and that the magnitude and duration of these effects differ as a function of the time at which the challenge is given.