title: Peripheral and central blockade of interleukin-6 trans-signaling differentially affects sleep architecture.
abstract: The immune system is known to essentially contribute to the regulation of sleep. Whereas research in this regard focused on the pro-inflammatory cytokines interleukin-1 and tumor necrosis factor, the role of interleukin-6 (IL-6) in sleep regulation has been less intensely studied, probably due to the so far seemingly ambiguous results. Yet, this picture might simply reflect that the effects of IL-6 are conveyed via two different pathways (with possibly different actions), i.e., in addition to the 'classical' signaling pathway via the membrane bound IL-6 receptor (IL-6R), IL-6 stimulates cells through the alternative 'trans-signaling' pathway via the soluble IL-6R. Here, we concentrated on the contributions of the trans-signaling pathway to sleep regulation. To characterize this contribution, we compared the effect of blocking IL-6 trans-signaling (by the soluble gp130Fc fusion protein) in the brain versus body periphery. Thus, we compared sleep in transgenic mice expressing the soluble gp130Fc protein only in the brain (GFAP mice) or in the body periphery (PEPCK mice), and in wild type mice (WT) during a 24-h period of undisturbed conditions and during 18 h following a 6-h period of sleep deprivation. Compared with WT mice, PEPCK mice displayed less sleep, particularly during the late light phase, and this was accompanied by decreases in slow wave sleep (SWS) and rapid eye movement (REM) sleep. Following sleep deprivation PEPCK mice primarily recovered REM sleep rather than SWS. GFAP mice showed a slight decrease in REM sleep in combination with a profound and persistent increase in EEG theta activity. In conclusion, peripheral and central nervous IL-6 trans-signaling differentially influences brain activity. Peripheral IL-6 trans-signaling appears to more profoundly contribute to sleep regulation, mainly by supporting SWS.
authors.affiliation: Institute of Medical Psychology and Behavioral Neurobiology, University of Tübingen, Germany; Graduate School of Neural & Behavioural Sciences, International Max Planck Research School, Tübingen, Germany.
authors.forename: Carlos N
authors.initials: CN
authors.lastname: Oyanedel
authors.affiliation: Institute of Medical Psychology and Behavioral Neurobiology, University of Tübingen, Germany; German Center for Diabetes Research (DZD), Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen (IDM), Tübingen, Germany.
authors.forename: Eduard
authors.initials: E
authors.lastname: Kelemen
authors.affiliation: Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Scheller
authors.affiliation: Institute of Medical Psychology and Behavioral Neurobiology, University of Tübingen, Germany; German Center for Diabetes Research (DZD), Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen (IDM), Tübingen, Germany; Center for Integrative Neuroscience, University of Tübingen, Germany. Electronic address: jan.born@uni-tuebingen.de.
authors.forename: Jan
authors.initials: J
authors.lastname: Born
authors.affiliation: Department of Biochemistry, University of Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000502:physiology*; D004569:Electroencephalography; D015850:Interleukin-6 / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011993:Recombinant Fusion Proteins / Q000235:genetics; D015398:Signal Transduction; D012890:Sleep / Q000276:immunology / Q000502:physiology*
chemical_list: D015850:Interleukin-6; D011993:Recombinant Fusion Proteins; C519852:olamkicept
keywords: IL-6 trans-signaling; REM sleep; Sleep; Slow wave activity; Slow wave sleep; Theta rhythm