Inhibition of interleukin-6 trans-signaling in the brain facilitates recovery from lipopolysaccharide-induced sickness behavior

• Published in: Journal of neuroinflammation Vol. 8; no. 1; p. 54
• Main Authors: Burton, Michael D, Sparkman, Nathan L, Johnson, Rodney W
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 19.05.2011; BioMed Central; BMC
• Subjects: Animals; Behavior, Animal - drug effects; Brain; Brain - metabolism; Cell Line; Cytokine Receptor gp130 - metabolism; Cytokine Receptor gp130 - pharmacology; Cytokines - metabolism; Exploratory Behavior - drug effects; Hippocampus - cytology; Hippocampus - metabolism; Illness Behavior - drug effects; Interleukin-6; Interleukin-6 - metabolism; Lipopolysaccharides - pharmacology; Male; Mice; Mice, Inbred BALB C; Microglia - cytology; Microglia - metabolism; Neural transmission; Neurons - cytology; Neurons - metabolism; Physiological aspects; Receptors, Interleukin-6 - metabolism; Signal Transduction - physiology; STAT3 Transcription Factor - metabolism; Toll-Like Receptor 4 - metabolism; United States
• ISSN: 1742-2094; 1742-2094
• DOI: 10.1186/1742-2094-8-54

Interleukin (IL)-6 is produced in the brain during peripheral infection and plays an important but poorly understood role in sickness behavior. Therefore, this study investigated the capacity of soluble gp130 (sgp130), a natural inhibitor of the IL-6 trans-signaling pathway to regulate IL-6 production in microglia and neurons in vitro and its effects on lipopolysaccharide (LPS)-induced sickness behavior in vivo. A murine microglia (BV.2) and neuronal cell line (Neuro.2A) were used to study the effects of stimulating and inhibiting the IL-6 signaling pathway in vitro. In vivo, adult (3-6 mo) BALB/c mice received an intracerebroventricular (ICV) injection of sgp130 followed by an intraperitoneal (i.p.) injection of LPS, and sickness behavior and markers of neuroinflammation were measured. Soluble gp130 attenuated IL-6- and LPS-stimulated IL-6 receptor (IL-6R) activation along with IL-6 protein release in both microglial (BV.2) and neuronal (Neuro.2A) cell types in vitro. Moreover, in vivo experiments showed that sgp130 facilitated recovery from LPS-induced sickness, and this sgp130-associated recovery was paralleled by reduced IL-6 receptor signaling, mRNA, and protein levels of IL-6 in the hippocampus. Taken together, the results show that sgp130 may exert an anti-inflammatory effect on microglia and neurons by inhibiting IL-6 binding. These data indicate that sgp130 inhibits the LPS-induced IL-6 trans-signal and show IL-6 and its receptor are involved in maintaining sickness behavior.