Abstract
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-γ (IFNγ),
IFNα, 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 GSK3β, but not
GSK3α. The regulatory mechanism involved GSK3β binding STAT3 and
promoting its association with the IFNγ receptor-associated
intracellular signaling complex responsible for activating STAT3. Furthermore,
GSK3β associated with the IFNγ receptor and was activated by
stimulation with IFNγ. Thus, inhibitors of GSK3 reduce the activation of
STAT3 and STAT5, providing a mechanism to differentially regulate STATs to
modulate the inflammatory response.
