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 several decades, has remained up until recently mechanistically obscure. The identification of a novel class of G-protein coupled receptors that negatively regulate the cyclic adenosine 3':5'-monophosphate (cAMP) cascade, bind cannabinoids, and are expressed on cells within the immune system has provided new insights into the mechanism for their biologic activity. Although the role of the cAMP cascade in the regulation of immune responses is itself highly controversial, a number of laboratories recently demonstrated that aberrant regulation of this signaling pathway leads to alterations in the expression of critical immunoregulatory genes, cell cycle arrest, and decreased immune function. This profile of effects is strikingly similar to that which is induced in leukocytes in the presence of cannabinoid compounds. In the present commentary, a putative mechanism of immune regulation by cannabinoids is proposed. This mechanism is discussed in the context of decreased cAMP signaling, the transcription factors that are consequently adversely regulated, and immunologically relevant genes that ultimately exhibit altered expression.