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

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

SUBMITTER: Downer EJ 

PROVIDER: S-EPMC3408184 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature