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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

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

Downer Eric J EJ Clifford Eileen E Amu Sylvie S Fallon Padraic G PG Moynagh Paul N PN

The Journal of biological chemistry 20120531 30

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. ...[more]

PMID: 22654113

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Project description:ABCA12 (ATP binding cassette transporter, family 12) is a cellular membrane transporter that facilitates the delivery of glucosylceramides to epidermal lamellar bodies in keratinocytes, a process that is critical for permeability barrier formation. Following secretion of lamellar bodies into the stratum corneum, glucosylceramides are metabolized to ceramides, which comprise approximately 50% of the lipid in stratum corneum. Gene mutations of ABCA12 underlie harlequin ichthyosis, a devastating skin disorder characterized by abnormal lamellar bodies and a severe barrier abnormality. Recently we reported that peroxisome proliferator-activated receptor (PPAR) and liver X receptor activators increase ABCA12 expression in human keratinocytes. Here we demonstrate that ceramide (C(2)-Cer and C(6)-Cer), but not C(8)-glucosylceramides, sphingosine, or ceramide 1-phosphate, increases ABCA12 mRNA expression in a dose- and time-dependent manner. Inhibitors of glucosylceramide synthase, sphingomyelin synthase, and ceramidase and small interfering RNA knockdown of human alkaline ceramidase, which all increase endogenous ceramide levels, also increased ABCA12 mRNA levels. Moreover, simultaneous treatment with C(6)-Cer and each of these same inhibitors additively increased ABCA12 expression, indicating that ceramide is an important inducer of ABCA12 expression and that the conversion of ceramide to other sphingolipids or metabolites is not required. Finally, both exogenous and endogenous ceramides preferentially stimulate PPARdelta expression (but not other PPARs or liver X receptors), whereas PPARdelta knockdown by siRNA transfection specifically diminished the ceramide-induced increase in ABCA12 mRNA levels, indicating that PPARdelta is a mediator of the ceramide effect. Together, these results show that ceramide, an important lipid component of epidermis, up-regulates ABCA12 expression via the PPARdelta-mediated signaling pathway, providing a substrate-driven, feed-forward mechanism for regulating this key lipid transporter.

Dataset Information

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

Publications

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

Similar Datasets

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