The synthetic cannabinoid R(+)WIN55,212-2 augments interferon-β expression via peroxisome proliferator-activated receptor-α.
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-β 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-α (PPARα) in mediating the effects of R(+)WIN55,212-2 on this pathway. Data herein demonstrate that the TLR3 agonist poly(I:C) promotes IFN-β expression and R(+)WIN55,212-2 enhances TLR3-induced IFN-β expression in a stereoselective manner via PPARα. R(+)WIN55,212-2 promotes increased transactivation and expression of PPARα. Using the PPARα antagonist GW6471, we demonstrate that R(+)WIN55,212-2 acts via PPARα to activate JNK, activator protein-1, and positive regulatory domain IV to transcriptionally regulate the IFN-β promoter. Furthermore, GW6471 ameliorated the protective effects of R(+)WIN55,212-2 during the initial phase of experimental autoimmune encephalomyelitis. Overall, these findings define PPARα as an important mediator in manifesting the effects of R(+)WIN55,212-2 on the signaling cascade regulating IFN-β expression. The study adds to our molecular appreciation of potential therapeutic effects of R(+)WIN55,212-2 in multiple sclerosis.
Institute of Immunology, National University of Ireland Maynooth, County Kildare, Ireland.
Eric J
EJ
Downer
Eileen
E
Clifford
Sylvie
S
Amu
Padraic G
PG
Fallon
Paul N
PN
Moynagh
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology*; D002186:Cannabinoids / Q000494:pharmacology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D007369:Interferon Inducers / Q000494:pharmacology; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000378:metabolism; D016899:Interferon-beta / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D009025:Morpholines / Q000494:pharmacology*; D009281:Naphthalenes / Q000494:pharmacology*; D010080:Oxazoles / Q000494:pharmacology; D047493:PPAR alpha / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D011070:Poly I-C / Q000494:pharmacology; D014443:Tyrosine / Q000031:analogs & derivatives / Q000494:pharmacology
D000700:Analgesics; D048588:Benzoxazines; D002186:Cannabinoids; C449302:GW 6471; C494232:IRF3 protein, human; D007369:Interferon Inducers; D050838:Interferon Regulatory Factor-3; C494233:Irf3 protein, mouse; D009025:Morpholines; D009281:Naphthalenes; D010080:Oxazoles; D047493:PPAR alpha; D014443:Tyrosine; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D016899:Interferon-beta; D011070:Poly I-C