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IFN-β Production by TLR4-Stimulated Innate Immune Cells Is Negatively Regulated by GSK3-β¹

Huizhi Wang^*, Carlos A. Garcia^*, Kunal Rehani^*, Caglar Cekic^*, Pascale Alard^*, Denis F. Kinane, Thomas Mitchell^*, and Michael Martin^2,*,

^* Department of Microbiology and Immunology and Institute for Cellular Therapeutics, University of Louisville School of Medicine, Louisville, KY 40202; Oral Health and Systemic Disease Research Group, University of Louisville School of Dentistry, Louisville, KY 40202

TLR 4 stimulation of innate immune cells induces a MyD88-independent signaling pathway that leads to the production of IFN-β. In this study, we demonstrate glycogen synthase kinase 3-β (GSK3-β) plays a fundamental role in this process. Suppression of GSK3-β activity by either pharmacological inhibition, small interfering RNA-mediated gene silencing, or ectopic expression of a kinase-dead GSK3-β mutant enhanced IFN-β production by TLR4-stimulated macrophages. Conversely, ectopic expression of a constitutively active GSK3-β mutant severely attenuated IFN-β production. GSK3-β was found to negatively control the cellular levels of the transcription factor c-Jun and its nuclear association with ATF-2. Small interfering RNA-mediated knockdown of c-Jun levels abrogated the ability of GSK3-β inhibition to augment IFN-β, demonstrating that the ability of GSK3 to control IFN-β production was due to its ability to regulate c-Jun levels. The ability of GSK3 inhibition to control IFN-β production was confirmed in vivo as mice treated with a GSK3 inhibitor exhibited enhanced systemic levels of IFN-β upon LPS challenge. These findings identify a novel regulatory pathway controlling IFN-β production by TLR4-stimulated innate immune cells.

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 This research was supported by Grant R01DE017680 from the National Institute of Dental Research.

² Address correspondence and reprint requests to Dr. Michael Martin, 501 South Preston Street, University of Louisville School of Dentistry Room 211A, Louisville, KY 40202. E-mail address: m0mart08{at}louisville.edu

³ Abbreviations used in this paper: GSK3-β, glycogen synthase kinase 3-β; BM-DM, bone marrow derived macrophage; siRNA, small interfering RNA.

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