Differential regulation of STAT family members by glycogen synthase kinase-3.
Excessive neuroinflammation contributes to many neurological disorders and is poorly controlled therapeutically. The signal transducer and activator of transcription (STAT) family of transcription factors has a central role in inflammatory reactions, being stimulated by multiple cytokines and interferons and regulating the expression of many proteins involved in inflammation. We found that STAT3 activation is highly dependent on glycogen synthase kinase-3 (GSK3). Inhibitors of GSK3 greatly reduced (>75%) the activating STAT3 tyrosine phosphorylation in mouse primary astrocytes, microglia, and macrophage-derived RAW264.7 cells induced by interferon-gamma (IFNgamma), IFNalpha, interleukin-6, or insulin. GSK3 inhibitors blocked STAT3 DNA binding activity and the expression of STAT3-induced GFAP and Bcl-3. GSK3 dependence was selective for activation of STAT3 and STAT5, whereas STAT1 and STAT6 activation were GSK3-independent. Knockdown of the two GSK3 isoforms showed STAT3 and STAT5 activation were dependent on GSK3beta, but not GSK3alpha. The regulatory mechanism involved GSK3beta binding STAT3 and promoting its association with the IFNgamma receptor-associated intracellular signaling complex responsible for activating STAT3. Furthermore, GSK3beta associated with the IFNgamma receptor and was activated by stimulation with IFNgamma. Thus, inhibitors of GSK3 reduce the activation of STAT3 and STAT5, providing a mechanism to differentially regulate STATs to modulate the inflammatory response.
Beurel
Eléonore
E
Department of Psychiatry and Behavioral Neurobiology, University of Alabama, Birmingham, Alabama 35294-0017, USA.
Jope
Richard S
RS
D000818:Animals; D001253:Astrocytes / Q000166:cytology; D002478:Cells, Cultured; D054728:Cucurbitacins / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism; D053612:Janus Kinases / Q000378:metabolism; D018021:Lithium Chloride / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D017471:Receptors, Interferon / Q000378:metabolism; D050791:STAT Transcription Factors / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000096743:Interferon gamma Receptor
D054728:Cucurbitacins; D038362:Glycogen Synthase Kinase 3; D007527:Isoenzymes; D053612:Janus Kinases; D018021:Lithium Chloride; D017471:Receptors, Interferon; D050791:STAT Transcription Factors; D050796:STAT3 Transcription Factor; D000096743:Interferon gamma Receptor; C494087:Stat3 protein, mouse