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-beta 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-alpha (PPAR alpha) in mediating the effects of R(+)WIN55,212-2 on this pathway. Data herein demonstrate that the TLR3 agonist poly(I:C) promotes IFN-beta expression and R(+)WIN55,212-2 enhances TLR3-induced IFN-beta expression in a stereoselective manner via PPAR alpha. R(+)WIN55,212-2 promotes increased transactivation and expression of PPAR alpha. Using the PPAR alpha antagonist GW6471, we demonstrate that R(+)WIN55,212-2 acts via PPAR alpha to activate JNK, activator protein-1, and positive regulatory domain IV to transcriptionally regulate the IFN-beta promoter. Furthermore, GW6471 ameliorated the protective effects of R(+) WIN55,212-2 during the initial phase of experimental autoimmune encephalomyelitis. Overall, these findings define PPAR alpha as an important mediator in manifesting the effects of R(+) WIN55,212-2 on the signaling cascade regulating IFN-beta expression. The study adds to our molecular appreciation of potential therapeutic effects of R(+)WIN55,212-2 in multiple sclerosis.