PT  - JOURNAL ARTICLE
AU  - Iris Lavon
AU  - Tatiana Sheinin
AU  - Sigal Meilin
AU  - Efrat Biton
AU  - Ayelet Weksler
AU  - Gilat Efroni
AU  - Avi Bar-Joseph
AU  - George Fink
AU  - Ayelet Avraham
TI  - A Novel Synthetic Cannabinoid Derivative Inhibits Inflammatory Liver Damage via Negative Cytokine Regulation
AID  - 10.1124/mol.64.6.1334
DP  - 2003 Dec 01
TA  - Molecular Pharmacology
PG  - 1334--1341
VI  - 64
IP  - 6
4099  - http://molpharm.aspetjournals.org/content/64/6/1334.short
4100  - http://molpharm.aspetjournals.org/content/64/6/1334.full
SO  - Mol Pharmacol2003 Dec 01; 64
AB  - The therapeutic potential of cannabinoids has been described previously for several inflammatory diseases, but the molecular mechanisms underlying the anti-inflammatory properties of cannabinoids are not well understood. In this study, we investigated the mechanism of action of a novel synthetic cannabinoid, [(+)(6aS,10aS)-6,6-Dimethyl-3-(1,1-dimethylheptyl)-1-hydroxy-9-(1H-imidazol-2-ylsulfanylmethyl]-6a,7,10,10a-tetrahydro-6H-dibenzo[b,d]pyran (PRS-211,092) that has no psychotropic effects but exhibits immunomodulatory properties. Treatment with PRS-211,092 significantly decreased Concanavalin A-induced liver injury in mice that was accompanied by: 1) promotion of early gene expression of interleukin (IL)-6 and IL-10 that play a protective role in this model; 2) induction of early gene expression of the suppressors of cytokine signaling (SOCS-1 and 3), followed by 3) inhibition of several pro-inflammatory mediators, including IL-2, monocyte chemoattractant protein-1 (MCP-1), IL-1β, interferon-γ, and tumor necrosis factor α. Based on these results, we propose a mechanism by which PRS-211,092 stimulates the expression of IL-6, IL-10 and the SOCS proteins that, in turn, negatively regulates the expression of pro-inflammatory cytokines. Negative regulation by PRS-211,092 was further demonstrated in cultured T cells, where it inhibited IL-2 production and nuclear factor of activated T cells activity. These findings suggest that this cannabinoid derivative is an immunomodulator that could be developed as a potential drug for hepatitis as well as for other short- or long-term inflammatory diseases.