Title

Activation and binding of peroxisome proliferator-activated receptor gamma by synthetic cannabinoid ajulemic acid

UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology; Department of Medicine, Division of Rheumatology

Publication Date

4-16-2003

Document Type

Article

Subjects

Adipocytes; Binding Sites; Cell Differentiation; Cells, Cultured; Humans; Interleukin-8; Promoter Regions (Genetics); Receptors, Cytoplasmic and Nuclear; Tetrahydrocannabinol; Transcription Factors

Disciplines

Life Sciences | Medicine and Health Sciences

Abstract

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 gamma (PPARgamma), a pharmacologically important member of the nuclear receptor superfamily. Functional assay indicates that AJA activates the transcriptional activity of both human and mouse PPARgamma at pharmacological concentrations. Activation of PPARgamma by AJA requires the AF-2 helix of the receptor, suggesting that AJA activates PPARgamma through the ligand-dependent AF-2 function. AJA binding consistently enables PPARgamma to recruit nuclear receptor coactivators. In addition, we show that AJA inhibits interleukin-8 promoter activity in a PPARgamma-dependent manner, suggesting a link between the anti-inflammatory action of AJA and the activation of PPARgamma. Finally, we find that AJA treatment induces differentiation of 3T3 L1 fibroblasts into adipocytes, a process mediated by PPARgamma. Together, these data indicate that PPARgamma 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 PPARgamma activation in multiple signaling pathways.

Rights and Permissions

Citation: Mol Pharmacol. 2003 May;63(5):983-92.

Related Resources

Link to Article in PubMed

Journal/Book/Conference Title

Molecular pharmacology

PubMed ID

12695526