Department of Biological Sciences, University of Lethbridge, Lethbridge, AB T1K 3M4, Canada.
Cells. 2022 Apr 20;11(9):1391. doi: 10.3390/cells11091391.
Cannabinoids, mainly cannabidiol (CBD) and Δ-tetrahydrocannabinol (THC), are the most studied group of compounds obtained from because of their several pharmaceutical properties. Current evidence suggests a crucial role of cannabinoids as potent anti-inflammatory agents for the treatment of chronic inflammatory diseases; however, the mechanisms remain largely unclear. Cytokine storm, a dysregulated severe inflammatory response by our immune system, is involved in the pathogenesis of numerous chronic inflammatory disorders, including coronavirus disease 2019 (COVID-19), which results in the accumulation of pro-inflammatory cytokines. Therefore, we hypothesized that CBD and THC reduce the levels of pro-inflammatory cytokines by inhibiting key inflammatory signaling pathways. The nucleotide-binding and oligomerization domain (NOD)-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome signaling has been implicated in a variety of chronic inflammatory diseases, which results in the release of pyroptotic cytokines, interleukin-1β (IL-1β) and IL-18. Likewise, the activation of the signal transducer and activator of transcription-3 (STAT3) causes increased expression of pro-inflammatory cytokines. We studied the effects of CBD and THC on lipopolysaccharide (LPS)-induced inflammatory response in human THP-1 macrophages and primary human bronchial epithelial cells (HBECs). Our results revealed that CBD and, for the first time, THC significantly inhibited NLRP3 inflammasome activation following LPS + ATP stimulation, leading to a reduction in the levels of IL-1β in THP-1 macrophages and HBECs. CBD attenuated the phosphorylation of nuclear factor-κB (NF-κB), and both cannabinoids inhibited the generation of oxidative stress post-LPS. Our multiplex ELISA data revealed that CBD and THC significantly diminished the levels of IL-6, IL-8, and tumor necrosis factor-α (TNF-α) after LPS treatment in THP-1 macrophages and HBECs. In addition, the phosphorylation of STAT3 was significantly downregulated by CBD and THC in THP-1 macrophages and HBECs, which was in turn attributed to the reduced phosphorylation of tyrosine kinase-2 (TYK2) by CBD and THC after LPS stimulation in these cells. Overall, CBD and THC were found to be effective in alleviating the LPS-induced cytokine storm in human macrophages and primary HBECs, at least via modulation of NLRP3 inflammasome and STAT3 signaling pathways. The encouraging results from this study warrant further investigation of these cannabinoids in vivo.
大麻素主要是大麻二酚（CBD）和Δ-四氢大麻酚（THC），是从大麻中提取的最具研究价值的化合物之一，因为它们具有多种药物特性。目前的证据表明，大麻素有作为治疗慢性炎症性疾病的有效抗炎药物的关键作用；然而，其机制仍在很大程度上尚不清楚。细胞因子风暴是我们免疫系统失调的一种严重炎症反应，涉及到许多慢性炎症性疾病的发病机制，包括 2019 年冠状病毒病（COVID-19），这会导致促炎细胞因子的积累。因此，我们假设 CBD 和 THC 通过抑制关键炎症信号通路来降低促炎细胞因子的水平。核苷酸结合寡聚化结构域（NOD）样受体家族含pyrin 结构域蛋白 3（NLRP3）炎性小体信号转导已被牵连到各种慢性炎症性疾病中，导致细胞焦亡细胞因子白细胞介素-1β（IL-1β）和白细胞介素-18 的释放。同样，信号转导和转录激活因子 3（STAT3）的激活导致促炎细胞因子的表达增加。我们研究了 CBD 和 THC 对脂多糖（LPS）诱导的人 THP-1 巨噬细胞和原代人支气管上皮细胞（HBECs）炎症反应的影响。我们的结果表明，CBD 和 THC 首次显著抑制 LPS+ATP 刺激后的 NLRP3 炎性小体激活，导致 THP-1 巨噬细胞和 HBECs 中 IL-1β水平降低。CBD 减弱了核因子-κB（NF-κB）的磷酸化，两种大麻素抑制 LPS 后氧化应激的产生。我们的多重 ELISA 数据显示，CBD 和 THC 显著降低了 LPS 处理后 THP-1 巨噬细胞和 HBECs 中白细胞介素-6（IL-6）、白细胞介素-8（IL-8）和肿瘤坏死因子-α（TNF-α）的水平。此外，CBD 和 THC 还显著下调了 THP-1 巨噬细胞和 HBECs 中 STAT3 的磷酸化，这归因于 LPS 刺激后 CBD 和 THC 对这些细胞中酪氨酸激酶-2（TYK2）的磷酸化减少。总的来说，CBD 和 THC 被发现能有效缓解 LPS 诱导的人巨噬细胞和原代 HBECs 中的细胞因子风暴，至少通过调节 NLRP3 炎性小体和 STAT3 信号通路。这项研究的令人鼓舞的结果需要进一步研究这些大麻素在体内的作用。
