IMMUNE REGULATION BY CANNABINOID COMPOUNDS THROUGH THE INHIBITION OF THE CYCLIC-AMP SIGNALING CASCADE AND ALTERED GENE-EXPRESSION

Immune modulation by cannabinoid compounds, although established for s everal decades, has remained up until recently mechanistically obscure . The identification of a novel class of G-protein coupled receptors t hat negatively regulate the cyclic adenosine 3':5'-monophosphate (cAMP ) cascade, bind cannabinoids, and are expressed on cells within the im mune system has provided new insights into the mechanism for their bio logic activity. Although the role of the cAMP cascade in the regulatio n of immune responses is itself highly controversial, a number of labo ratories recently demonstrated that aberrant regulation of this signal ing pathway leads to alterations in the expression of critical immunor egulatory genes, cell cycle arrest, and decreased immune function. Thi s profile oi effects is strikingly similar to that which is induced in leukocytes in the presence of cannabinoid compounds. In the present c ommentary, a putative mechanism of immune regulation by cannabinoids i s proposed. This mechanism is discussed in the context of decreased cA MP signaling, the transcription factors that are consequently adversel y regulated, and immunologically relevant genes that ultimately exhibi t altered expression.