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 canna binoid receptors in immune modulation by cannabinoid compounds. The pr imary focus is on the signal transduction events that are initiated fo llowing ligand binding to cannabinoid receptors and how these events l ead to detrimental effects on the normal responsiveness of immunocompe tent cells. Toward this end, signalling events are traced from the can nabinoid receptor to the transcription factors which are adversely reg ulated in the presence of cannabinoid compounds during leukocyte activ ation. Moreover, this aberrant regulation of transcription factors is discussed in the context of altered gene expression and the impact thi s has on leukocyte function. Lastly, an important goal of this article is to dispel a long standing myth that the cyclic adenosine 3':5'-mon ophosphate (cAMP) cascade is a negative regulatory pathway for immunoc ompetent cells. This chapter examines two major immunologic cell-types which are well established as exhibiting altered function following c annabinoid 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 canna binoids in spite of the fact that this cell-type expresses functional cannabinoid receptors [Schatz, A.R., Koh, W.S., Kaminski, N.E., 1993. Delta(9)-tetrahydrocannabinol selectively inhibits T-cell dependent hu moral immune responses through direct inhibition of accessory T-cell f unction. Immunopharmacol., 26, pp. 129-137.]. One cautionary note, alt hough the focus of this article is on cannabinoid receptor mediated si gnalling events, immune modulation by cannabinoid compounds is likely multi-factorial presumably involving receptor as well as receptor-nonr elated events. Effects on leukocytes by cannabinoids which are believe d to be mediated by receptor-nonrelated events are outside the scope o f this paper and will not be discussed. One last introductory paint is that even though their is presumably little overlap in the genes whic h are regulated by cannabinoids in leukocytes as compared to other cel l-types (e.g., neural cells), the major signalling pathways involved i n cellular regulation are ubiquitous. With that in mind, it is likely that their is a considerable amount of similarity in the signalling pa thways regulated by cannabinoids in cell-types of different lineage, g iven that they express cannabinoid receptors. In this context, signall ing events observed in leukocytes can provide important insight into w hich genes may be modulated by cannabinoid in other cell types. (C) 19 98 Elsevier Science B.V.