NDLI: Glucocorticoids inhibit IRF3 phosphorylation in response to Toll-like receptor-3 and -4 by targeting TBK1 activation.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	O'neill, Luke A. J. Mccoy, Claire E. Carpenter, Susan Pålsson-mcdermott, Eva M. Gearing, Linden J.
Description	Author Affiliation: McCoy CE ( School of Biochemistry and Immunology, Trinity College Dublin, Dublin 2, Ireland. cmccoy@tcd.ie)
Abstract	Phosphorylation of the transcription factor interferon regulatory factor 3 (IRF3) is essential for the induction of promoters which contain the interferon-stimulated response element (ISRE). IRF3 can be activated by Toll-like receptor 3 (TLR3) in response to the double-stranded RNA mimic poly(I-C) and by TLR4 in response to lipopolysaccharide (LPS). Here we have analyzed the effect of the glucocorticoid dexamethasone on this response. Dexamethasone inhibited the induction of the ISRE-dependent gene RANTES (regulated on activation normal T cell expressed and secreted) in both U373-CD14 cells and human peripheral blood mononuclear cells and also an ISRE luciferase construct, activated by either TLR3 or TLR4. It also inhibited increased phosphorylation of IRF3 in its N terminus in response to LPS and in its C terminus on Ser-396 in response to either poly(I-C) or LPS. Several dexamethasone-induced phosphatases were tested for possible involvement in these effects; MKP1 did not appear to be involved, although MKP2 and MKP5 both partially inhibited induction of the ISRE, pointing to their possible involvement in the effect of dexamethasone. Importantly, we found that dexamethasone could inhibit TBK1 kinase activity and TBK1 phosphorylation on Ser-172, both of which are required for IRF3 phosphorylation downstream of TLR3 and TLR4 stimulation. Our study, therefore, demonstrates that TBK1 is a target for dexamethasone, common to both TLR3 and TLR4 signaling.
ISSN	00219258
e-ISSN	1083351X
Journal	Journal of Biological Chemistry
Issue Number	21
Volume Number	283
Language	English
Publisher	American Society for Biochemistry and Molecular Biology (United States)
Publisher Date	2008-05-23
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Glucocorticoids Pharmacology Interferon Regulatory Factor-3 Metabolism Protein-Serine-Threonine Kinases Toll-Like Receptor 3 Toll-Like Receptor 4 Cells, Cultured Chemokine CCL5 Genetics Dextroamphetamine Dimerization Enzyme Activation Gene Expression Regulation Drug Effects Genes, Reporter Lipopolysaccharides Phosphorylation Poly I-C Research Support, Non-U.S. Gov't Biochemistry Molecular Biology
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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