The recognition that exogenous cannabinoids could alter immune functional activities through cannabinoid receptors implicated the existence of an endogenous functionally relevant ligand-receptor system. Devane et al. (1992) isolated from porcine brain an arachidonic derivative, anandamide, in a screen for endogenous ligands for the cannabinoid receptor with properties suggestive that it acted as a natural ligand for the cannabinoid receptor in the brain. The discovery and characterization of anandamide served as a catalyst for studies to assess its role in signaling through the CB1 receptor in the brain as well as in the immune system. Valk et al. (1997) reported that anandamide acted through the CB2 receptor as a synergistic growth factor for hematopoietic cells. Derocq et al. (1998), in a similar study using IL-3-dependent and IL-6-dependent murine cell lines, postulated that anandamide exerted a growth-promotion effect. However, it was indicated that this growth-promoting effect was cannabinoid receptor-independent.
De Petrocellis et al. (1998) reported that anandamide potently and selectively inhibited the proliferation of human breast cancer cells in vitro. Anandamide dose-dependently suppressed the proliferation of MCF-7 and EFM-19 human breast carcinoma cells but did not affect the proliferation of several nonmam-mary tumoral cell lines. The anti-proliferative effect of anandamide was apparently not due to toxicity or to apoptosis of cells but was accompanied by a reduction of cells in the S phase of the cell cycle. The stable analog of anandamide R-methanandamide and the synthetic cannabinoid HU-210 also inhibited EFM-19 cell proliferation. The drug effects were blocked with the CBi antagonist SR141716A, suggesting that anandamide blocked human breast cancer cell proliferation through a CB1 -like receptor-mediated inhibition of endogenous prolactin action at the level of the prolactin receptor. Facci et al. (1995) reported that mast cells, multifunctional bone marrow-derived cells found in mucosal and connective tissues and in the nervous system that play an important role in tissue inflammation and neuroimmune interactions, expressed a peripheral cannabinoid receptor with differential sensitivity to anandamide and palmitoylethanolamide. It was found that they expressed the CB2 receptor and that this receptor exerted negative regulatory effects on mast cell activation. Although palmitoylethanolamide and anandamide bound to the CB2 receptor, only the former down-modulated mast cell activation in vitro. It was proposed that palmitoylethanolamide, unlike anandamide, behaved as an endogenous agonist for the CB2 receptor on mast cells. The existence of an autacoid local inflammation antagonism (ALIA) pro cess was proposed. However, more recent experiments have shown that palmi-toylethanolamide has very low affinity for CB2 receptors and little CB2 receptor efficacy (Griffin et al. 2000; Lambert et al. 1999; Sheskin et al. 1997; Showalter et al. 1996).
In 1995, Mechoulam et al. (1995) identified an endogenous 2-monoglyceride from canine gut that bound to cannabinoid receptors which was designated 2-AG. Studies using 2-AG have indicated that it is more active than anandamide in the immune system. Lee et al. (1995) reported that 2-AG suppressed lympho-proliferation of splenocytes to LPS and anti-CD3 at concentrations greater than 10 pM. Proliferation due to alloantigen stimulation also was suppressed, but no suppression of PMA/ionomycin-induced proliferation was observed. In addition, the in vitro PFC response to SRBC was increased by 2-AG. Sugiura et al. (2000) examined the effect of 2-AG on intracellular free Ca2+ concentrations in the human macrophage-like cells HL-60 and found that it induced a rapid transient increase in levels of intracellular free Ca2+. The Ca2+ transient induced by 2-AG was blocked by pretreatment of the HL-60 cells with SR144528, the CB2 antagonist, but not with SR141716A, the CBi antagonist, indicating the involvement of the CB2 receptor in this cellular response. Anandamide and palmitoylethanolamide, other putative endogenous ligands, were found to be a weak partial agonist and an inactive lig-and, respectively. Based on these results, Sugiura et al. (2000) proposed that the CB2 receptor was originally a 2-AG receptor, and that 2-AG constituted its native cognate ligand.
Diaz et al. (1994) examined mechanisms of action of THC in inducing im-munosuppression contextual to transductional activities mediated through lipid bioeffector molecule derivatives of arachidonic acid, since THC was known to affect arachidonic acid metabolism in non-lymphoid cells. It was indicated that THC increased the production of the eicosanoid 12-hydroxyeicosateraenoic acid (12-HETE) from peripheral blood mononuclear cells (PBMC). To determine if other eicosanoid metabolites were affected by THC, levels of leukotriene B4 were measured. THC was shown to increase markedly the production of LTB4 from PBMC stimulated with the calcium ionophore A23187. The collective results indicated that THC altered arachidonic acid metabolism in lymphocytes by increasing the production of lipoxygenase products, biological effectors with known immuno-suppressive properties (reviewed in Lawrence et al. 2002).
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