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J. Biol. Chem., Vol. 283, Issue 32, 21934-21944, August 8, 2008

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Differential Regulation of STAT Family Members by Glycogen Synthase Kinase-3^*

From the Department of Psychiatry and Behavioral Neurobiology, University of Alabama, Birmingham, Alabama 35294-0017

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- (IFN), IFN, 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 GSK3. The regulatory mechanism involved GSK3β binding STAT3 and promoting its association with the IFN receptor-associated intracellular signaling complex responsible for activating STAT3. Furthermore, GSK3β associated with the IFN receptor and was activated by stimulation with IFN. Thus, inhibitors of GSK3 reduce the activation of STAT3 and STAT5, providing a mechanism to differentially regulate STATs to modulate the inflammatory response.

Received for publication, March 31, 2008 , and in revised form, May 14, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants AG021045, MH38752, and NS37768. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Psychiatry and Behavioral Neurobiology, Sparks Center 1057, 1720 Seventh Ave. 5., University of Alabama, Birmingham, AL 35294-0017. Tel.: 205-934-7023; Fax: 205-934-3709; E-mail: jope{at}uab.edu.

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