Tags

Type your tag names separated by a space and hit enter

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.
J Biol Chem 2011; 286(12):10316-28JB

Abstract

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.

Authors+Show Affiliations

Institute of Immunology, National University of Ireland Maynooth, Co. Kildare, Ireland.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21245146

Citation

Downer, Eric J., et al. "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." The Journal of Biological Chemistry, vol. 286, no. 12, 2011, pp. 10316-28.
Downer EJ, Clifford E, Gran B, et al. 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. J Biol Chem. 2011;286(12):10316-28.
Downer, E. J., Clifford, E., Gran, B., Nel, H. J., Fallon, P. G., & Moynagh, P. N. (2011). 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. The Journal of Biological Chemistry, 286(12), pp. 10316-28. doi:10.1074/jbc.M110.188599.
Downer EJ, et al. 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. J Biol Chem. 2011 Mar 25;286(12):10316-28. PubMed PMID: 21245146.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Downer,Eric J, AU - Clifford,Eileen, AU - Gran,Bruno, AU - Nel,Hendrik J, AU - Fallon,Padraic G, AU - Moynagh,Paul N, Y1 - 2011/01/18/ PY - 2011/1/20/entrez PY - 2011/1/20/pubmed PY - 2011/6/10/medline SP - 10316 EP - 28 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 286 IS - 12 N2 - 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. SN - 1083-351X UR - https://www.unboundmedicine.com/medline/citation/21245146/abstract/Identification_of_the_synthetic_cannabinoid_R_+_WIN55212_2_as_a_novel_regulator_of_IFN_regulatory_factor_3__IRF3__activation_and_IFN_{beta}_expression:_relevance_to_therapeutic_effects_in_models_of_multiple_sclerosis_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=21245146 DB - PRIME DP - Unbound Medicine ER -