Burnette-Curley D, Cabral G A
Department of Microbiology and Immunology, Virginia Commonwealth University/Medical College of Virginia, Richmond 23298-0678, USA.
Proc Soc Exp Biol Med. 1995 Oct;210(1):64-76. doi: 10.3181/00379727-210-43926.
delta 9tetrahydrocannabinol (THC), the major psychoactive component of marijuana, has been shown to inhibit macrophage cell contact-dependent cytolysis of tumor cells. The purpose of this study was to determine whether THC inhibited macrophage cytolytic function by targeting selectively tumor necrosis factor (TNF)-dependent pathways versus L-arginine-dependent reactive nitrogen intermediates. An in vitro system employing RAW264.7 macrophage-like cells as effectors and TNF-sensitive mouse L929 fibroblasts or nitric oxide (NO.)-sensitive P815 mastocytoma cells as targets, was employed to assess the effect of THC on cytolysis. Macrophages were pretreated with THC or vehicle for 48 hr, subjected to multistep activation with 10 U/ml recombinant mouse gamma-interferon (IFN-gamma) plus 100 ng/ml LPS or to direct activation with 1 microgram/ml LPS, and co-cultured with tumor cells in the presence or absence of THC. THC inhibited TNF-dependent killing by macrophages subjected to either multistep or direct activation. Decreased amounts of TNF-alpha were detected in medium of macrophage cultures treated with THC. In contrast, THC inhibited NO.-dependent cell contact killing only for macrophages subjected to direct activation. Decreased levels of NO2-, a stable degradation product of the short-lived and highly toxic effector molecule NO., were produced by these macrophages. In addition, the effect of the enantiomeric pairs (-)CP55,940/(+)CP56,667 or (-)HU-210/(+)HU-211 on macrophage cell contact-dependent killing was assessed. Inhibition of macrophage tumoricidal activity against TNF-sensitive L929 cells was effected by both isomers of THC analogs. In contrast, both of the enantiomeric pairs had an effect on killing of NO.-sensitive P815 mastocytoma cells only for macrophages subjected to direct activation. These data suggest that cannabinoids inhibit macrophage cell contact-dependent killing of tumor cells by a noncannabinoid receptor-mediated mechanism. However, specific cytolytic pathways are inhibited differentially by cannabinoids depending on the activation stimuli to which macrophages are exposed.
δ9-四氢大麻酚（THC）是大麻的主要精神活性成分，已被证明能抑制巨噬细胞对肿瘤细胞的接触依赖性细胞溶解作用。本研究的目的是确定THC是否通过选择性靶向肿瘤坏死因子（TNF）依赖性途径与L-精氨酸依赖性反应性氮中间体来抑制巨噬细胞的细胞溶解功能。采用一种体外系统，以RAW264.7巨噬细胞样细胞作为效应细胞，以TNF敏感的小鼠L929成纤维细胞或一氧化氮（NO.）敏感的P815肥大细胞瘤细胞作为靶细胞，来评估THC对细胞溶解的影响。巨噬细胞用THC或赋形剂预处理48小时，用10 U/ml重组小鼠γ-干扰素（IFN-γ）加100 ng/ml脂多糖进行多步激活，或用1μg/ml脂多糖直接激活，然后在有或无THC的情况下与肿瘤细胞共培养。THC抑制了经多步或直接激活的巨噬细胞的TNF依赖性杀伤作用。在用THC处理的巨噬细胞培养物的培养基中检测到TNF-α的量减少。相比之下，THC仅对经直接激活的巨噬细胞的NO.依赖性细胞接触杀伤有抑制作用。这些巨噬细胞产生的NO2-（一种短寿命且剧毒的效应分子NO.的稳定降解产物）水平降低。此外，还评估了对映体对（-）CP55,940/（+）CP56,667或（-）HU-210/（+）HU-211对巨噬细胞接触依赖性杀伤的影响。THC类似物的两种异构体均对巨噬细胞对TNF敏感的L929细胞的杀肿瘤活性有抑制作用。相比之下，这两对映体仅对经直接激活的巨噬细胞对NO.敏感的P815肥大细胞瘤细胞的杀伤有影响。这些数据表明，大麻素通过非大麻素受体介导的机制抑制巨噬细胞对肿瘤细胞的接触依赖性杀伤。然而，根据巨噬细胞所暴露的激活刺激，大麻素对特定细胞溶解途径的抑制作用存在差异。
