Zhu W, Newton C, Daaka Y, Friedman H, Klein T W
Department of Medical Microbiology and Immunology, University of South Florida, College of Medicine, Tampa.
J Pharmacol Exp Ther. 1994 Sep;270(3):1334-9.
Interleukin (IL) 1 is a pleiotropic cytokine and an important mediator of various physiological responses including the acute phase response, inflammation, lymphocyte function and certain central nervous system responses. Because delta 9-tetrahydrocannabinol (THC) treatment also has been reported to affect these physiological responses, we tested the drug effect on IL1 production and secretion. Addition of THC to endotoxin (ETX)-treated murine, resident peritoneal macrophage cultures increased, in a dose-dependent manner, supernatant IL1 activity over ETX only treatment. Treatment with THC alone had no effect. Enzyme-linked immunosorbent assay studies and specific antibody neutralization studies demonstrated both IL1 alpha and IL1 beta were increased by drug treatment. The steady-state levels of cellular IL1 alpha and IL1 beta mRNAs, determined by Northern blotting and reverse transcription-polymerase chain reaction, were unchanged, suggesting the possibility THC was not increasing IL1 production. To examine this possibility further, ETX-activated macrophages, pulsed-labeled with 35S-methionine, were chased for 2, 4 and 6 hr in the presence of THC and the levels of the various IL1 bioforms determined by immunoprecipitation. These results showed THC treatment had no effect on the level of ETX-induced intracellular promature IL1 alpha and IL1 beta proteins; however, a THC-induced increase and prolongation of release of promature IL1 alpha and mature IL1 beta were observed. The immunoprecipitation results were confirmed by studies examining supernatant bioactivity. These results suggest THC augments the ETX-induced processing of IL1 beta and release of IL1 alpha rather than increasing the cellular production of IL1 protein.(ABSTRACT TRUNCATED AT 250 WORDS)
白细胞介素（IL）-1是一种多效性细胞因子，是多种生理反应的重要介质，包括急性期反应、炎症、淋巴细胞功能及某些中枢神经系统反应。由于已有报道称δ9-四氢大麻酚（THC）治疗也会影响这些生理反应，我们测试了该药物对IL-1产生和分泌的影响。在内毒素（ETX）处理的小鼠腹腔常驻巨噬细胞培养物中添加THC，与仅用ETX处理相比，能以剂量依赖的方式增加上清液中IL-1的活性。单独使用THC处理则无效果。酶联免疫吸附测定研究和特异性抗体中和研究表明，药物处理可使IL-1α和IL-1β均增加。通过Northern印迹法和逆转录-聚合酶链反应测定的细胞IL-1α和IL-1β mRNA的稳态水平未发生变化，提示THC可能并未增加IL-1的产生。为进一步研究这种可能性，用35S-甲硫氨酸脉冲标记ETX激活的巨噬细胞，在存在THC的情况下追踪2、4和6小时，并通过免疫沉淀法测定各种IL-1生物形式的水平。这些结果表明，THC处理对ETX诱导的细胞内前体IL-1α和IL-1β蛋白水平没有影响；然而，观察到THC诱导前体IL-1α和成熟IL-1β的释放增加并延长。通过检测上清液生物活性的研究证实了免疫沉淀结果。这些结果表明，THC增强了ETX诱导的IL-1β加工和IL-1α释放，而不是增加IL-1蛋白的细胞产生。（摘要截短至250字）
