Regulation of the cAMP cascade, gene expression and immune function by cannabinoid receptors

The objective of this article is to discuss the putative role of cannabinoid receptors in immune modulation by cannabinoid compounds. The primary focus is on the signal transduction events that are initiated following ligand binding to cannabinoid receptors and how these events lead to detrimental effects on the normal responsiveness of immunocompetent cells. Toward this end, signalling events are traced from the cannabinoid receptor to the transcription factors which are adversely regulated in the presence of cannabinoid compounds during leukocyte activation. Moreover, this aberrant regulation of transcription factors is discussed in the context of altered gene expression and the impact this has on leukocyte function. Lastly, an important goal of this article is to dispel a long standing myth that the cyclic adenosine 3':5'-monophosphate (cAMP) cascade is a negative regulatory pathway for immunocompetent cells. This chapter examines two major immunologic cell-types which are well established as exhibiting altered function following cannabinoid treatment, helper T-cells and the macrophage. Not discussed are the effects of cannabinoids on B-cell function. This is primarily due to the rather refractory nature of B-cells to inhibition by cannabinoids in spite of the fact that this cell-type expresses functional cannabinoid receptors [Schatz, A.R., Koh, W.S., Kaminski, N.E., 1993. Delta9-tetrahydrocannabinol selectively inhibits T-cell dependent humoral immune responses through direct inhibition of accessory T-cell function. Immunopharmacol., 26, pp. 129-137.]. One cautionary note, although the focus of this article is on cannabinoid receptor mediated signalling events, immune modulation by cannabinoid compounds is likely multi-factorial presumably involving receptor as well as receptor-nonrelated events. Effects on leukocytes by cannabinoids which are believed to be mediated by receptor-nonrelated events are outside the scope of this paper and will not be discussed. One last introductory point is that even though their is presumably little overlap in the genes which are regulated by cannabinoids in leukocytes as compared to other cell-types (e.g., neural cells), the major signalling pathways involved in cellular regulation are ubiquitous. With that in mind, it is likely that their is a considerable amount of similarity in the signalling pathways regulated by cannabinoids in cell-types of different lineage, given that they express cannabinoid receptors. In this context, signalling events observed in leukocytes can provide important insight into which genes may be modulated by cannabinoid in other cell types.