Vol. 63, Issue 5, 983-992, May 2003

Activation and Binding of Peroxisome Proliferator-Activated Receptor  by Synthetic Cannabinoid Ajulemic Acid

Jilin Liu, Hui Li, Sumner H. Burstein, Robert B. Zurier, and J. Don Chen¹

Departments of Biochemistry and Molecular Pharmacology (J.L., H.L., S.H.B., J.D.C.) and Medicine (R.B.Z.), University of Massachusetts Medical School, Worcester, Massachusetts

Ajulemic acid (AJA) is a synthetic analog of the tetrahydrocannabinol (THC) metabolite THC-11-oic acid; THC is a major active ingredient of the drug marijuana derived from the plant cannabis. AJA has potent analgesic and anti-inflammatory activity without the psychotropic action of THC. Unlike the nonsteroidal anti-inflammatory drugs, AJA is not ulcerogenic at therapeutic doses, making it a promising anti-inflammatory drug. However, the mechanism of AJA action remains unknown. Here we report that AJA binds directly and specifically to the peroxisome proliferator-activated receptor  (PPAR), a pharmacologically important member of the nuclear receptor superfamily. Functional assay indicates that AJA activates the transcriptional activity of both human and mouse PPAR at pharmacological concentrations. Activation of PPAR by AJA requires the AF-2 helix of the receptor, suggesting that AJA activates PPAR through the ligand-dependent AF-2 function. AJA binding consistently enables PPAR to recruit nuclear receptor coactivators. In addition, we show that AJA inhibits interleukin-8 promoter activity in a PPAR-dependent manner, suggesting a link between the anti-inflammatory action of AJA and the activation of PPAR. Finally, we find that AJA treatment induces differentiation of 3T3 L1 fibroblasts into adipocytes, a process mediated by PPAR. Together, these data indicate that PPAR may be a molecular target for AJA, providing a potential mechanism for the anti-inflammatory action of AJA, and possibly other cannabinoids. These studies also implicate other potential therapeutic actions of AJA through PPAR activation in multiple signaling pathways.