Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USA; Institute for Integrative Toxicology, Michigan State University, East Lansing, MI 48824, USA.
Institute for Integrative Toxicology, Michigan State University, East Lansing, MI 48824, USA.
Toxicol Appl Pharmacol. 2019 Apr 15;369:82-89. doi: 10.1016/j.taap.2019.02.013. Epub 2019 Feb 23.
Plasmacytoid dendritic cells (pDC) compose 0.2-0.5% of circulating leukocytes but play a significant role in mounting host immune responses. Elevated and chronic activation of pDC are implicated in autoimmune disease like systemic lupus erythematosus and rheumatoid arthritis. Δ-tetrahydrocannabinol (THC) is a well characterized cannabinoid with potent anti-inflammatory activity, but acceptance of THC as a treatment for autoimmune disorders has been hindered due to psychotropic activity. The psychotropic effects of THC are mediated through cannabinoid receptor 1 (CB1) expressed in the central nervous system while the immunomodulatory effects of THC result from THC binding to CB1 and CB2 on immune cells. Synthetic CB2-selective agonists have been developed to explore immune modulation by cannabinoids in the absence of psychotropic effects. The goal of these studies was to determine if the CB2-selective agonists, JWH-015 and JWH-133, have comparable efficacy to THC in modulating IFNα and TNFα responses by primary human pDC. Treatment with JWH-133 and JWH-015 inhibited CpG-induced IFNα and TNFα responses by pDC. Further, the phosphorylation of IRF7, TBK1, NFκB, and IKKγ, key events in pDC activation, were suppressed by THC, JWH-133, and JWH-015. Likewise, the phosphorylation of AKT at the S473 and T308 residues were differentially modulated by treatment with THC and both JWH compounds. Collectively, these results demonstrate the potential for CB2 targeted therapeutics for treatment of inflammatory conditions involving aberrant pDC activity.
浆细胞样树突状细胞（pDC）占循环白细胞的 0.2-0.5%，但在宿主免疫反应中起着重要作用。pDC 的升高和慢性激活与自身免疫性疾病如系统性红斑狼疮和类风湿关节炎有关。Δ-四氢大麻酚（THC）是一种具有很强抗炎活性的特征明确的大麻素，但由于其精神活性，接受 THC 作为自身免疫性疾病的治疗方法受到了阻碍。THC 的精神活性作用是通过中枢神经系统中表达的大麻素受体 1（CB1）介导的，而 THC 对免疫细胞的免疫调节作用则是由于 THC 与 CB1 和 CB2 的结合。已经开发出合成的 CB2 选择性激动剂来探索大麻素在没有精神活性作用的情况下对免疫的调节作用。这些研究的目的是确定 CB2 选择性激动剂 JWH-015 和 JWH-133 是否具有与 THC 相当的调节 IFNα 和 TNFα 反应的功效。JWH-133 和 JWH-015 的治疗抑制了 pDC 对 CpG 诱导的 IFNα 和 TNFα 反应。此外，IRF7、TBK1、NFκB 和 IKKγ 的磷酸化，pDC 激活的关键事件，也被 THC、JWH-133 和 JWH-015 抑制。同样，AKT 在 S473 和 T308 残基上的磷酸化也被 THC 和两种 JWH 化合物的处理不同地调节。总之，这些结果表明 CB2 靶向治疗在治疗涉及异常 pDC 活性的炎症性疾病方面具有潜力。
