| Identification of the synthetic cannabinoid R(+)WIN55,212-2 as a novel regulator of IFN regulatory factor 3 activation and IFN-beta expression: relevance to therapeutic effects in models of multiple sclerosis. | |
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MedLine Citation:
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PMID: 21245146 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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β-Interferons (IFN-βs) represent one of the first line treatments for relapsing-remitting multiple sclerosis, slowing disease progression while 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, whereas 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, whereas down-regulating 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. |
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Authors:
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Eric J Downer; Eileen Clifford; Bruno Gran; Hendrik J Nel; Padraic G Fallon; Paul N Moynagh |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2011-01-18 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 286 ISSN: 1083-351X ISO Abbreviation: J. Biol. Chem. Publication Date: 2011 Mar |
Date Detail:
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Created Date: 2011-04-01 Completed Date: 2011-06-09 Revised Date: 2012-03-26 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 10316-28 Citation Subset: IM |
Affiliation:
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Institute of Immunology, National University of Ireland Maynooth, Co. Kildare, Ireland. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adult Analgesics / pharmacology* Animals Benzoxazines / pharmacology* Cannabinoids / pharmacology* Cell Line, Tumor Encephalomyelitis, Autoimmune, Experimental / genetics, metabolism Female Gene Expression Regulation / drug effects* HEK293 Cells Humans Interferon Regulatory Factor-3 / biosynthesis*, genetics Interferon-beta / biosynthesis*, genetics Male Mice Mice, Knockout Middle Aged Morpholines / pharmacology* Multiple Sclerosis / drug therapy*, genetics, metabolism Naphthalenes / pharmacology* Toll-Like Receptor 3 / genetics, metabolism Toll-Like Receptor 4 / genetics, metabolism |
| Chemical | |
Reg. No./Substance:
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0/Analgesics; 0/Benzoxazines; 0/Cannabinoids; 0/IRF3 protein, human; 0/Interferon Regulatory Factor-3; 0/Irf3 protein, mouse; 0/Morpholines; 0/Naphthalenes; 0/TLR3 protein, human; 0/TLR3 protein, mouse; 0/TLR4 protein, human; 0/Tlr4 protein, mouse; 0/Toll-Like Receptor 3; 0/Toll-Like Receptor 4; 134959-51-6/Win 55212-2; 77238-31-4/Interferon-beta |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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