Pharmacological characterisation of cannabinoid receptors inhibiting interleukin 2 release from human peripheral blood mononuclear cells

Abstract

The effects of a range of cannabinoid receptor agonists and antagonists on phytohaemagglutinin-induced secretion of interleukin-2 from human peripheral blood mononuclear cells were investigated. The nonselective cannabinoid receptor agonist WIN55212-2 (( R)-(+)-[2,3-dihydro-5-methyl-3-[4-morpholinylmethyl]pyrrolo[1,2,3-de]1,4-benzoxazin-6-yl](1-naphthyl) methanone mesylate) and the selective cannabinoid CB 2 receptor agonist JWH 015 ((2-methyl-1-propyl-1 H-indol-3-yl)-1-napthalenylmethanone) inhibited phytohaemagglutinin (10 μg/ml)-induced release of interleukin-2 in a concentration-dependent manner (IC 1/2max, WIN55212-2=8.8×10 −7 M, 95% confidence limits (C.L.)=2.2×10 −7–3.5×10 −6 M; JWH 015=1.8×10 −6 M, 95% C.L.=1.2×10 −6–2.9×10 −6 M, n=5). The nonselective cannabinoid receptor agonists CP55,940 ((−)-3-[2-hydroxy-4-(1,1-dimethyl-hepthyl)-phenyl]4-[3-hydroxypropyl]cyclo-hexan-1-ol), Δ 9-tetrahydrocannabinol and the selective cannabinoid CB 1 receptor agonist ACEA (arachidonoyl-2-chloroethylamide) had no significant ( P>0.05) inhibitory effect on phytohaemagglutinin-induced release of interleukin-2. Dexamethasone significantly ( P<0.05) inhibited phytohaemagglutinin-induced release of interleukin-2 in a concentration-dependent manner (IC 1/2max=1.3×10 −8 M, 95% C.L.=1.4×10 −9–3.2×10 −8 M). The cannabinoid CB 1 receptor antagonist SR141716A ( N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1 H-pyrazole-3-carboxamide hydrochloride) (10 −6 M) did not antagonise the inhibitory effect of WIN55212-2 whereas the cannabinoid CB 2 receptor antagonist SR144528 ( N-(1, S)-endo-1,3,3-trimethyl bicyclo(2,2,1)heptan-2-yl)-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide) antagonised the inhibitory effect of WIN55212-2 (p A 2=6.3±0.1, n=5). In addition, CP55,940 (10 −6 M) and Δ 9-tetrahydrocannabinol (10 −6 M) also antagonised the inhibitory effects of WIN55212-2 (p A 2=6.1±0.1, n=5 and p A 2=6.9±0.2, n=5). In summary, WIN55,212-2 and JWH 015 inhibited interleukin-2 release from human peripheral blood mononuclear cells via the cannabinoid CB 2 receptor. In contrast, CP55,940 and Δ 9-tetrahydrocannabinol behaved as partial agonists/antagonists in these cells.