The synthetic cannabinoid R(+)WIN55,212-2 augments interferon-β expression via peroxisome proliferator-activated receptor-α.

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-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.

• Authors: Eric J Downer, Eileen Clifford, Sylvie Amu, Padraic G Fallon, Paul N Moynagh
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 287 Issue 30 Pg. 25440-53 (Jul 20 2012) ISSN: 1083-351X [Electronic] United States
• PMID: 22654113 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Analgesics
• Benzoxazines
• Cannabinoids
• GW 6471
• IRF3 protein, human
• Interferon Inducers
• Interferon Regulatory Factor-3
• Irf3 protein, mouse
• Morpholines
• Naphthalenes
• Oxazoles
• PPAR alpha
• Tyrosine
• (3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
• Interferon-beta
• Poly I-C

Topics

• Analgesics (pharmacology)
• Animals
• Benzoxazines (pharmacology)
• Cannabinoids (pharmacology)
• Encephalomyelitis, Autoimmune, Experimental (genetics, metabolism)
• Gene Expression Regulation (drug effects, genetics)
• HEK293 Cells
• Humans
• Interferon Inducers (pharmacology)
• Interferon Regulatory Factor-3 (genetics, metabolism)
• Interferon-beta (biosynthesis, genetics)
• Mice
• Morpholines (pharmacology)
• Naphthalenes (pharmacology)
• Oxazoles (pharmacology)
• PPAR alpha (agonists, genetics, metabolism)
• Poly I-C (pharmacology)
• Tyrosine (analogs & derivatives, pharmacology)