Lipopolysaccharide-induced interleukin-6 production is controlled by glycogen synthase kinase-3 and STAT3 in the brain.
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 IL-6 was the cytokine most diminished (>90%) by GSK3 inhibition. Inhibition of GSK3, and knockdown of GSK3beta, not GSK3alpha, 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.


CONCLUSIONS
STAT3 and GSK3 cooperatively promote neuroinflammation, providing novel targets for anti-inflammatory intervention.
Beurel
Eléonore
E
Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294-0017, USA. eleonore_beurel@hotmail.fr
Jope
Richard S
RS
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D004926:Escherichia coli; D055785:Gene Knockdown Techniques; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007249:Inflammation / Q000139:chemically induced; D015850:Interleukin-6 / Q000097:blood / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity*; D018020:Lithium Compounds / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009457:Neuroglia / Q000187:drug effects / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D018805:Sepsis / Q000503:physiopathology
D016207:Cytokines; D005904:Glial Fibrillary Acidic Protein; D015850:Interleukin-6; D008070:Lipopolysaccharides; D018020:Lithium Compounds; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D038362:Glycogen Synthase Kinase 3