Neurobiology Department, Weizmann Institute of Science, 76100 Rehovot, Israel.
J Biol Chem. 2010 Jan 15;285(3):1616-26. doi: 10.1074/jbc.M109.069294. Epub 2009 Nov 12.
Cannabinoids have been shown to exert anti-inflammatory activities in various in vivo and in vitro experimental models as well as ameliorate various inflammatory degenerative diseases. However, the mechanisms of these effects are not completely understood. Using the BV-2 mouse microglial cell line and lipopolysaccharide (LPS) to induce an inflammatory response, we studied the signaling pathways engaged in the anti-inflammatory effects of cannabinoids as well as their influence on the expression of several genes known to be involved in inflammation. We found that the two major cannabinoids present in marijuana, Delta(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD), decrease the production and release of proinflammatory cytokines, including interleukin-1beta, interleukin-6, and interferon (IFN)beta, from LPS-activated microglial cells. The cannabinoid anti-inflammatory action does not seem to involve the CB1 and CB2 cannabinoid receptors or the abn-CBD-sensitive receptors. In addition, we found that THC and CBD act through different, although partially overlapping, mechanisms. CBD, but not THC, reduces the activity of the NF-kappaB pathway, a primary pathway regulating the expression of proinflammatory genes. Moreover, CBD, but not THC, up-regulates the activation of the STAT3 transcription factor, an element of homeostatic mechanism(s) inducing anti-inflammatory events. Following CBD treatment, but less so with THC, we observed a decreased level of mRNA for the Socs3 gene, a main negative regulator of STATs and particularly of STAT3. However, both CBD and THC decreased the activation of the LPS-induced STAT1 transcription factor, a key player in IFNbeta-dependent proinflammatory processes. In summary, our observations show that CBD and THC vary in their effects on the anti-inflammatory pathways, including the NF-kappaB and IFNbeta-dependent pathways.
大麻素已被证明在各种体内和体外实验模型中具有抗炎活性，并能改善各种炎症性退行性疾病。然而，这些作用的机制尚不完全清楚。本研究使用 BV-2 小鼠小胶质细胞系和脂多糖（LPS）诱导炎症反应，研究了大麻素抗炎作用所涉及的信号通路，以及它们对几种已知参与炎症的基因表达的影响。我们发现，大麻中存在的两种主要大麻素，Δ9-四氢大麻酚（THC）和大麻二酚（CBD），可降低 LPS 激活的小胶质细胞中促炎细胞因子（包括白细胞介素-1β、白细胞介素-6 和干扰素（IFN）β）的产生和释放。大麻素的抗炎作用似乎不涉及 CB1 和 CB2 大麻素受体或 abn-CBD 敏感受体。此外，我们发现 THC 和 CBD 通过不同的机制发挥作用，尽管部分重叠。CBD 而不是 THC 可降低 NF-κB 途径的活性，该途径是调节促炎基因表达的主要途径。此外，CBD 而不是 THC 可上调 STAT3 转录因子的激活，这是诱导抗炎事件的体内平衡机制的一部分。在用 CBD 处理后，但用 THC 处理后则不然，我们观察到 Socs3 基因的 mRNA 水平降低，该基因是 STATs 的主要负调节剂，尤其是 STAT3。然而，CBD 和 THC 均可降低 LPS 诱导的 STAT1 转录因子的激活，该因子是 IFNβ 依赖性促炎过程中的关键因子。综上所述，我们的观察结果表明，CBD 和 THC 在抗炎途径（包括 NF-κB 和 IFNβ 依赖性途径）的作用不同。
