Lipopolysaccharide-induced interleukin-6 production is controlled by glycogen synthase kinase-3 and STAT3 in the brain
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BioMed Central
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Lipopolysaccharide-induced interleukin-6 production is controlled by glycogen synthase kinase-3 and STAT3 in the brain Eléonore Beurel and Richard S Jope* Address: Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294-0017, USA Email: Eléonore Beurel - [email protected]; Richard S Jope* - [email protected] * Corresponding author
Published: 11 March 2009 Journal of Neuroinflammation 2009, 6:9
doi:10.1186/1742-2094-6-9
Received: 7 February 2009 Accepted: 11 March 2009
This article is available from: http://www.jneuroinflammation.com/content/6/1/9 © 2009 Beurel and Jope; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract Background: Septic shock is a prevalent condition that, when not lethal, often causes disturbances in cognition, mood, and behavior, particularly due to central actions of the inflammatory cytokine interleukin-6 (IL-6). To identify potential targets to control brain IL-6, we tested if IL-6 produced by glia is regulated by signal transducer and activator of transcription-3 (STAT3) and glycogen synthase kinase-3 (GSK3). Methods: Lipopolysaccharide (LPS) was used to induce inflammatory responses in mice or cultured primary glia. IL-6 was measured by ELISA and other inflammatory molecules were measured using an array. Results: Mouse brain IL-6 levels increased after central, as well as peripheral, LPS administration, consistent with glia producing a portion of brain IL-6. STAT3 in the brain was activated after peripheral or central LPS administration, and in LPS-stimulated cultured primary glia. Inhibition of STAT3 expression, function, or activation reduced by ~80% IL-6 production by primary glia, demonstrating the dependence on active STAT3. GSK3 promotes STAT3 activation, and array analysis of inflammatory molecules produced by LPS-stimulated primary glia demonstrated that IL6 was the cytokine most diminished (>90%) by GSK3 inhibition. Inhibition of GSK3, and knockdown of GSK3β, not GSK3α, greatly inhibited IL-6 production by LPS-stimulated primary glia. Conversely, expression of active STAT3 and active GSK3 promoted IL-6 production. In vivo inhibition of GSK3 reduced serum and brain IL-6 levels, brain STAT3 activation, and GFAP upregulation following LPS administration. Conclusion: STAT3 and GSK3 cooperatively promote neuroinflammation, providing novel targets for anti-inflammatory intervention.
Background The inflammatory system is hyperactivated during sepsis, a potentially lethal condition induced by bacterial infection that affects nearly 1 million people in the United States every year [1]. Inflammation is controlled by a balance of activating and inhibitory signals delivered intrac-
ellularly by transmembrane receptors that recognize
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