Downer, Eric J. and Clifford, Eileen and Gran, Bruno and Hendrik, J. Nel and Fallon, Padraig G. and Moynagh, Paul N. (2011) Identification of the Synthetic Cannabinoid R()WIN55,212-2 as a Novel Regulator of IFN Regulatory Factor 3 Activation and IFN- Expression. Journal of Biological Chemistry, 286 (12). pp. 10316-10328. ISSN 0021-9258

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Abstract

Beta Interferons (IFN-βs) represent one of the first line treatments for relapsing remitting multiple sclerosis (RRMS), slowing disease progression whilst reducing the frequency of relapses. Despite this, more effective, well tolerated therapeutic strategies are needed. Cannabinoids palliate experimental autoimmune encephalomyelitis (EAE) symptoms and have therapeutic potential in MS patients although the precise molecular mechanism for these effects is not understood. Toll-like receptor (TLR) signaling controls innate immune responses and TLRs are implicated in MS. Here we demonstrate that the synthetic cannabinoid R(+)WIN55,212-2 is a novel regulator of TLR3 and TLR4 signaling by inhibiting the pro-inflammatory signaling axis triggered by TLR3 and TLR4 whilst selectively augmenting TLR3-induced activation of IFN regulatory factor 3 (IRF3) and expression of IFN-β. We present evidence that R(+)WIN55,212-2 strongly promotes the nuclear localization of IRF3. The potentiation of IFN-β expression by R(+)WIN55,212-2 is critical for manifesting its protective effects in the murine MS model EAE as evidenced by its reduced therapeutic efficacy in the presence of an anti-IFN-β antibody. R(+)WIN55,212-2 also induces IFN-β expression in MS patient peripheral blood mononuclear cells (PBMCs), whilst downregulating inflammatory signaling in these cells. These findings identify R(+)WIN55,212-2 as a novel regulator of TLR3 signaling to IRF3 activation and IFN-β expression and highlights a new mechanism that may be open to exploitation in the development of new therapeutics for the treatment of MS.

Item Type:	Article
Additional Information:	JBC Papers in Press. Published on January 18, 2011 as Manuscript M110.188599. The latest version is at http://www.jbc.org/cgi/doi/10.1074/jbc.M110.188599
Keywords:	Synthetic Cannabinoid; R(+)WIN55 212-2 ;Novel Regulator; IFN Regulatory Factor 3; IFN- Expression; Therapeutic Effects; Multiple Sclerosis; Experimental autoimmune encephalomyelitis; Toll-like receptor;
Academic Unit:	Faculty of Science and Engineering > Biology Faculty of Science and Engineering > Research Institutes > Institute of Immunology
Item ID:	4267
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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