Effects on the Immune System 411cess was proposed. However, more recent experiments have shown that palmi-
toylethanolamide has very low affinity for CB 2 receptors and little CB 2 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 μM. 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 CB 2 antagonist, but not with
SR141716A, the CB 1 antagonist, indicating the involvement of the CB 2 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
CB 2 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 af-
fect 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 mea-
sured. 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).
7
Cannabinoids as Immune Therapeutic Agents
Cannabinoids, as immunosuppressive compounds, have been proposed as having
therapeutic potential in chronic inflammatory disorders and neurodegenerative
disease triggered by inflammatory attack. Lyman et al. (1989) inoculated Lewis
rats and strain 13 guinea pigs with myelin-basic protein emulsified in complete
Freund’s adjuvant to induce experimental autoimmune encephalomyelitis (EAE)
to mimic MS and indicated that THC-treated animals had either no clinical signs
or exhibited mild signs with delayed onset and greater survival. Examination