GSK-3 mediates the release of IL-1β, TNF-α and IL-10 from cortical glia.
Neuroinflammation has been shown to contribute to neurodegenerative and psychiatric disorders such as Alzheimer's disease and major depression due to the inappropriate release of pro-inflammatory cytokines from activated microglia. The precise molecular events that mediate cytokine release from glia remain unknown but we suggest that the serine/threonine kinase glycogen synthase kinase-3 (GSK-3) may be involved. The aim of this study therefore was to investigate the effect of lipopolysaccharide (LPS) on expression and activity of the GSK-3β isoform in glia, and to assess if GSK-3 mediates the LPS-induced change in inflammatory cytokine levels in culture medium from rat glial-enriched cortical cultures. GSK-3β was expressed in microglia and astrocytes, and stimulation of these cultures with LPS induced an increase in GSK-3β expression and activity, and in pro-inflammatory cytokine levels in culture media. We show that GSK-3 inhibition using a small molecule inhibitor SB216763 or the mood stabiliser lithium chloride reduced the LPS-induced elevated levels of pro-inflammatory cytokines present in culture media from rat glial-enriched cortical cultures. These results demonstrate a role for GSK-3 as a modulator of inflammatory cytokine levels in the brain, and contribute to a mechanistic insight into neurological disorders in which neuroinflammation is a characteristic feature.
Department of Anatomy and Neuroscience, University College Cork, Ireland. hollygreenie@gmail.com
Holly F
HF
Green
Yvonne M
YM
Nolan
D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism*; D018920:Coculture Techniques; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D016753:Interleukin-10 / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism*; D009457:Neuroglia / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3