Downer, Eric J. and Clifford, Eileen and Amu, Sylvie and Fallon, Padraic G. and Moynagh, Paul N. (2012) The Synthetic Cannabinoid R(+)WIN55,212-2 Augments Interferon-β Expression via Peroxisome Proliferator-activated Receptor-α. Journal of Biological Chemistry, 287 (30). pp. 25440-25453. ISSN 0021-9258

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Abstract

We have demonstrated that R()WIN55,212-2, a synthetic cannabinoid that possesses cannabimimetic properties, acts as a novel regulator of Toll-like receptor 3 (TLR3) signaling to interferon (IFN) regulatory factor 3 (IRF3) activation and IFN- expression, and this is critical for manifesting its protective effects in a murine multiple sclerosis model. Here we investigated the role of peroxisome proliferator-activated receptor- (PPAR) in mediating the effects of R()WIN55,212-2 on this pathway. Data herein demonstrate that the TLR3 agonist poly(I:C) promotes IFN- expression and R()WIN55,212-2 enhances TLR3-induced IFN- expression in a stereoselective manner via PPAR. R()WIN55,212-2 promotes increased transactivation and expression of PPAR. Using the PPAR antagonist GW6471, we demonstrate that R()WIN55,212-2 acts via PPAR to activate JNK, activator protein-1, and positive regulatory domain IV to transcriptionally regulate the IFN- promoter. Furthermore, GW6471 ameliorated the protective effects of R()WIN55,212-2 during the initial phase of experimental autoimmune encephalomyelitis. Overall, these findings define PPAR as an important mediator in manifesting the effects of R()WIN55,212-2 on the signaling cascade regulating IFN- expression. The study adds to our molecular appreciation of potential therapeutic effects of R()WIN55,212-2 in multiple sclerosis.

Item Type:	Article
Additional Information:	The definitive version of this article is available at DOI 10.1074/jbc.M112.371757 . This work was supported by Science Foundation Ireland (to P. N. M.) and an IRCSET postdoctoral fellowship (to E. J. D.).
Keywords:	Synthetic Cannabinoid; Interferon-β; Expression; Peroxisome; Proliferator-activated; Receptor-α; Toll-like receptor 3;
Academic Unit:	Faculty of Science and Engineering > Biology
Item ID:	4266
Depositing User:	Professor Paul Moynagh
Date Deposited:	20 Mar 2013 16:53
Journal or Publication Title:	Journal of Biological Chemistry
Publisher:	American Society for Biochemistry and Molecular Biology
Refereed:	Yes
URI:	http://www.asbmb.org/page.aspx?id=598
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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