PT Unknown
AU May, U
TI Role of IL-6 trans-signalling for sleep-wake behaviour of rats: generation of brain-specific sgp130-Fc transgenic mice ; central blockade of IL-6 trans-signalling
PY 2010
PU Christian-Albrechts-Universität zu Kiel
WP https://macau.uni-kiel.de/receive/diss_mods_00005150
LA en
DE sleep; IL-6 trans-signalling; Hyper-IL-6; sgp130; transgenic mice; Schlaf; IL-6-Trans-Signalling; transgene Mäuse
AB The cytokine Interleukin 6 (IL-6) is involved in many biological functions of the immune system, metabolism and the central nervous system, and in the bidirectional communication between these systems. In the brain, IL-6 is considered to affect the modulation of sleep-wake behaviour and synaptic plasticity. IL-6 is further well characterised for its dual role to maintain homeostasis as well as to contribute to inflammatory and autoimmune processes, both in brain and periphery. Signal transduction of IL-6 is induced by binding of IL-6 to the membrane-bound IL-6 receptor (IL-6R; classic signalling) or alternatively to the soluble form of the IL-6R (sIL-6R; trans-signalling). The membrane-bound glycoprotein 130 (gp130) is the signal-transducing receptor subunit in both signalling modes. Gp130 is ubiquitously expressed throughout the body, whereas IL-6R expression is restricted to distinct cell populations. Within the brain parenchyma the IL-6R is sparsely expressed, and thus the brain is primarily reliant on trans-signalling in its response to IL-6. 
As a previous study revealed an upregulation of the peripheral sIL-6R in humans during sleep (Dimitrov et al., 2006), the influence of IL-6 trans-signalling on sleep regulation/modulation was scrutinised in this work initially. The effect of the IL-6 trans-signalling mimetic designer cytokine Hyper-IL-6 (sIL-6R coupled to IL-6) was investigated on sleep architecture of rats by EEG/EMG sleep recordings. Hyper-IL-6 can activate almost all cells of the brain in contrast to IL-6 itself. Results of this present work demonstrated that an intracerebroventricular injection of Hyper-IL-6 (500 ng) before the dark phase into rats led to increased amounts of REM sleep accompanied by a reduced EEG power density. Non-REM sleep was not affected. These data define a new function of IL-6 trans-signalling within the complex network of REM sleep modulation. That might further be of importance for altered sleep behaviour under pathophysiological conditions in which sIL-6R and IL-6 are elevated (e.g. bacterial/viral infections, major depression). 
A further approach to explore the impact of IL-6 trans-signalling on brain-regulated functions included the central “knock-out” of this signal transduction mode. For that purpose transgenic mice were generated in this work expressing the competitive antagonist of IL-6 trans-signalling sgp130-Fc under transcriptional control of the astrocyte-specific promoter gfa2 within the brain. The protein sgp130-Fc is a dimer of the human extracellular part of gp130 fused to the Fc-portion of a human IgG antibody. Expression and secretion of sgp130-Fc in the brain of transgenic mice on the protein level could be verified. The biological activity of the transgenic sgp130-Fc protein was confirmed by Hyper-IL-6 precipitation tests. Likewise, the protein amounts of sgp130-Fc appeared to be sufficient for the blockade of sIL-6R-mediated cellular responses in the brain. The presence of sgp130-Fc mRNA in transgenic animals was detected predominantly in the brain. However, sgp130-Fc was also found in sera of the three different established mouse lines at varying protein levels, which did not correlate with the amounts observed within the brain. 
The gfa2–sgp130-Fc transgenic mice generated in this work offer an useful “in vivo tool” to further study the relevance of IL-6 trans-signalling for sleep-wake behaviour, memory consolidation, and models of peripheral and neuropathological inflammation.
PI Kiel
ER