The mechanism by which cannabidiol (CBD) suppresses TNF-α secretion involves inappropriate localization of TNF-α converting enzyme (TACE)

IF 3.7 4区 医学 Q2 CELL BIOLOGY
Christa M. Frodella , Liyuan Liu , Wei Tan , Stephen B. Pruett , Barbara L.F. Kaplan
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Abstract

Cannabidiol (CBD) is a phytocannabinoid derived from Cannabis sativa that exerts anti-inflammatory mechanisms. CBD is being examined for its putative effects on the neuroinflammatory disease, multiple sclerosis (MS). One of the major immune mediators that propagates MS and its mouse model experimental autoimmune encephalomyelitis (EAE) are macrophages. Macrophages can polarize into an inflammatory phenotype (M1) or an anti-inflammatory phenotype (M2a). Therefore, elucidating the impact on macrophage polarization with CBD pre-treatment is necessary to understand its anti-inflammatory mechanisms. To study this effect, murine macrophages (RAW 264.7) were pre-treated with CBD (10 µM) or vehicle (ethanol 0.1 %) and were either left untreated (naive; cell media only), or stimulated under M1 (IFN-γ + lipopolysaccharide, LPS) or M2a (IL-4) conditions for 24 hr. Cells were analyzed for macrophage polarization markers, and supernatants were analyzed for cytokines and chemokines. Immunofluorescence staining was performed on M1-polarized cells for the metalloprotease, tumor necrosis factor-α-converting enzyme (TACE), as this enzyme is responsible for the secretion of TNF-α. Overall results showed that CBD decreased several markers associated with the M1 phenotype while exhibiting less effects on the M2a phenotype. Significantly, under M1 conditions, CBD increased the percentage of intracellular and surface TNF-α but decreased secreted TNF-α. This phenomenon might be mediated by TACE as staining showed that CBD sequestered TACE intracellularly. CBD also prevented RelA nuclear translocation. These results suggest that CBD may exert its anti-inflammatory effects by reducing M1 polarization and decreasing TNF-α secretion via inappropriate localization of TACE and RelA.

大麻二酚(CBD)抑制 TNF-α 分泌的机制涉及 TNF-α 转换酶(TACE)的不当定位
大麻二酚(CBD)是从大麻中提取的一种植物大麻素,具有抗炎机制。目前正在研究大麻二酚对神经炎症性疾病多发性硬化症(MS)的潜在影响。巨噬细胞是传播多发性硬化症及其小鼠模型实验性自身免疫性脑脊髓炎(EAE)的主要免疫介质之一。巨噬细胞可极化为炎症表型(M1)或抗炎表型(M2a)。因此,有必要阐明 CBD 预处理对巨噬细胞极化的影响,以了解其抗炎机制。为了研究这种影响,小鼠巨噬细胞(RAW 264.7)用 CBD(10 µM)或载体(乙醇 0.1 %)预处理,然后不处理(天真;仅细胞介质),或在 M1(IFN-γ + 脂多糖,LPS)或 M2a(IL-4)条件下刺激 24 小时。对细胞进行巨噬细胞极化标记分析,并对上清液进行细胞因子和趋化因子分析。对 M1 极化细胞进行了金属蛋白酶、肿瘤坏死因子-α-转化酶(TACE)的免疫荧光染色,因为这种酶负责分泌 TNF-α。总体结果显示,CBD 可减少与 M1 表型相关的几种标记物,对 M2a 表型的影响较小。值得注意的是,在 M1 条件下,CBD 增加了细胞内和表面 TNF-α 的百分比,但减少了分泌的 TNF-α。这一现象可能是由 TACE 介导的,因为染色显示 CBD 在细胞内封闭了 TACE。CBD 还阻止了 RelA 的核转位。这些结果表明,CBD 可通过 TACE 和 RelA 的不适当定位,减少 M1 极化和 TNF-α 的分泌,从而发挥其抗炎作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cellular immunology
Cellular immunology 生物-免疫学
CiteScore
8.20
自引率
2.30%
发文量
102
审稿时长
30 days
期刊介绍: Cellular Immunology publishes original investigations concerned with the immunological activities of cells in experimental or clinical situations. The scope of the journal encompasses the broad area of in vitro and in vivo studies of cellular immune responses. Purely clinical descriptive studies are not considered. Research Areas include: • Antigen receptor sites • Autoimmunity • Delayed-type hypersensitivity or cellular immunity • Immunologic deficiency states and their reconstitution • Immunologic surveillance and tumor immunity • Immunomodulation • Immunotherapy • Lymphokines and cytokines • Nonantibody immunity • Parasite immunology • Resistance to intracellular microbial and viral infection • Thymus and lymphocyte immunobiology • Transplantation immunology • Tumor immunity.
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