Abstract
BackgroundSeptic 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).MethodsLipopolysaccharide (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.ResultsMouse 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 IL-6 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.ConclusionSTAT3 and GSK3 cooperatively promote neuroinflammation, providing novel targets for anti-inflammatory intervention.
Highlights
Septic shock is a prevalent condition that, when not lethal, often causes disturbances in cognition, mood, and behavior, due to central actions of the inflammatory cytokine interleukin-6 (IL-6)
These findings indicate that strategies to reduce IL-6 production may be valuable for protecting the central nervous system (CNS) from damage caused by sepsis
IL-6 robustly accumulates in the brain after sepsis IL-6 in the cerebral cortex, cerebellum, and hippocampus was markedly increased 4 hr after peripheral LPS administration, which reflected the increased serum IL-6 level, whereas LPS administration slightly increased cortical and serum levels of TNFα, but not of IL-1β, at this time (Figure 1A–C)
Summary
Septic shock is a prevalent condition that, when not lethal, often causes disturbances in cognition, mood, and behavior, due to central actions of the inflammatory cytokine interleukin-6 (IL-6). Increased brain IL-6 has been associated with severe cognitive impairments [8,9,10] and likely contributes to the cognitive and neuroanatomical long-term consequences of sepsis, such as persistent behavioral deficits and neuronal loss [11]. These findings indicate that strategies to reduce IL-6 production may be valuable for protecting the CNS from damage caused by sepsis
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
