Chang Y H, Lee S T, Lin W W
Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
J Cell Biochem. 2001;81(4):715-23. doi: 10.1002/jcb.1103.
Delta(9)-Tetrahydrocannabinol (Delta(9)-THC) is the major psychoactive component of marijuana and elicits pharmacological actions via cannabinoid receptors. Anandamide (AEA) and 2-arachidonoyl-glycerol (2-AG) are endogenous ligands for cannabinoid receptors, which because of their structural similarities to arachidonic acid (AA), AEA, and 2-AG could serve as substrates for lipoxygenases and cyclooxygenases (COXs) that metabolize polyunsaturated fatty acids to potent bioactive molecules. In this study, we have compared the effects of Delta(9)-THC, AEA, 2-AG, and another cannabinoid agonist, indomethacin morpholinylamide (IMMA), on lipopolysaccharide (LPS)-induced NO, IL-6, and PGE(2) release from J774 macrophages. Delta(9)-THC, IMMA, and AEA diminish LPS-induced NO and IL-6 production in a concentration-dependent manner. 2-AG inhibits the production of IL-6 but slightly increases iNOS-dependent NO production. Delta(9)-THC and IMMA also inhibit LPS-induced PGE(2) production and COX-2 induction, while AEA and 2-AG have no effects. These discrepant results of 2-AG on iNOS and COX-2 induction might be due to its bioactive metabolites, AA and PGE(2), whose incubation cause the potentiation of both iNOS and COX-2 induction. On the contrary, the AEA metabolite, PGE(2)-ethanolamide, influences neither the LPS-induced NO nor IL-6 production. Taken together, direct cannabinoid receptor activation leads to anti-inflammatory action via inhibition of macrophage function. The endogenous cannabinoid, 2-AG, also serves as a substrate for COX-catalyzing PGE(2) production, which in turn modulates the action of CB2.
Δ⁹-四氢大麻酚（Δ⁹-THC）是大麻的主要精神活性成分，通过大麻素受体引发药理作用。花生四烯乙醇胺（AEA）和2-花生四烯酸甘油酯（2-AG）是大麻素受体的内源性配体，由于它们与花生四烯酸（AA）在结构上相似，AEA和2-AG可作为脂氧合酶和环氧化酶（COXs）的底物，这些酶将多不饱和脂肪酸代谢为强效生物活性分子。在本研究中，我们比较了Δ⁹-THC、AEA、2-AG和另一种大麻素激动剂吲哚美辛吗啉酰胺（IMMA）对脂多糖（LPS）诱导的J774巨噬细胞释放一氧化氮（NO）、白细胞介素-6（IL-6）和前列腺素E₂（PGE₂）的影响。Δ⁹-THC、IMMA和AEA以浓度依赖性方式减少LPS诱导的NO和IL-6产生。2-AG抑制IL-6的产生，但略微增加诱导型一氧化氮合酶（iNOS）依赖性NO的产生。Δ⁹-THC和IMMA也抑制LPS诱导的PGE₂产生和COX-2的诱导，而AEA和2-AG则无此作用。2-AG对iNOS和COX-2诱导的这些不同结果可能是由于其生物活性代谢产物AA和PGE₂，它们的孵育会导致iNOS和COX-2诱导的增强。相反，AEA的代谢产物PGE₂-乙醇酰胺对LPS诱导的NO和IL-6产生均无影响。综上所述，直接激活大麻素受体可通过抑制巨噬细胞功能产生抗炎作用。内源性大麻素2-AG也是COX催化PGE₂产生的底物，进而调节CB2的作用。
