Acidic Cannabinoids Suppress Proinflammatory Cytokine Release by Blocking Store-operated Calcium Entry.
Acidic Cannabinoids Suppress Proinflammatory Cytokine Release by Blocking Store-operated Calcium Entry.
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DOI：
10.1093/function/zqac033
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发表时间：
2022
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影响因子：
--
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中科院分区：
文献类型：
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人们早就知道大麻会影响许多生物活动。虽然植物提取物、纯化大麻素或合成大麻素类似物已显示出治疗疼痛、炎症、癫痫、食欲刺激、肌肉痉挛和恶心/呕吐的潜力，但其潜在的作用机制仍不明确。在这项研究中，我们首次全面概述了全植物大麻提取物和各种纯大麻素对几种不同免疫细胞系储存操作钙（Ca2+）进入（SOCE）的影响。储存操作的Ca2+进入是免疫细胞中最重要的Ca2+内流机制之一，它对T淋巴细胞的激活至关重要，导致促炎细胞因子的释放，介导炎症和T细胞增殖，这是维持慢性疼痛的关键机制。虽然两种主要的大麻素大麻二酚和反式-Δ9-tetrahydrocannabinol在抑制SOCE方面基本上无效，但我们首次报道了几种次要的大麻素，主要是羧酸衍生物，特别是大麻酚酸，通过阻断钙释放激活的钙电流，显示出对SOCE的高效能。此外，我们发现SOCE的抑制导致活化T细胞的核因子活化和人T淋巴细胞中白细胞介素2的产生减少。综上所述，这些结果表明大麻素介导的促炎靶点如SOCE的抑制可能至少部分解释了大麻的抗炎和镇痛作用。储存操作钙进入是由受体(R)刺激介导的，由酪氨酸激酶（TK）或G蛋白(G)转导，导致磷脂酶C的激活和肌醇1,4,5三磷酸（IP3）的产生。IP3受体（IP3R）在内质网（ER）中的开放导致STIM1/2感知的储存耗尽，其通过钙释放激活钙（CRAC）通道激活钙（Ca2+）内流。几种大麻素（CBx）抑制这些CRAC通道，从而抑制钙调素(CaM) -钙调磷酸酶(CaN) -活化T细胞核因子（NFAT）通路的信号转导，从而调节细胞因子释放和细胞增殖。
Cannabis sativa has long been known to affect numerous biological activities. Although plant extracts, purified cannabinoids, or synthetic cannabinoid analogs have shown therapeutic potential in pain, inflammation, seizure disorders, appetite stimulation, muscle spasticity, and treatment of nausea/vomiting, the underlying mechanisms of action remain ill-defined. In this study we provide the first comprehensive overview of the effects of whole-plant Cannabis extracts and various pure cannabinoids on store-operated calcium (Ca2+) entry (SOCE) in several different immune cell lines. Store-operated Ca2+ entry is one of the most significant Ca2+ influx mechanisms in immune cells, and it is critical for the activation of T lymphocytes, leading to the release of proinflammatory cytokines and mediating inflammation and T cell proliferation, key mechanisms for maintaining chronic pain. While the two major cannabinoids cannabidiol and trans-Δ9-tetrahydrocannabinol were largely ineffective in inhibiting SOCE, we report for the first time that several minor cannabinoids, mainly the carboxylic acid derivatives and particularly cannabigerolic acid, demonstrated high potency against SOCE by blocking calcium release-activated calcium currents. Moreover, we show that this inhibition of SOCE resulted in a decrease of nuclear factor of activated T-cells activation and Interleukin 2 production in human T lymphocytes. Taken together, these results indicate that cannabinoid-mediated inhibition of a proinflammatory target such as SOCE may at least partially explain the anti-inflammatory and analgesic effects of Cannabis. Store-Operated Calcium Entry is mediated by receptor (R) stimulation, transduced by tyrosine kinases (TK) or G proteins (G), leading to activation of phospholipase C and inositol 1,4,5 trisphosphate (IP3) production. The opening of IP3 receptors (IP3R) in the endoplasmic reticulum (ER) results in store depletion that is sensed by STIM1/2, which activate calcium (Ca2+) influx via Calcium Release-Activated Calcium (CRAC) channels. Several cannabinoids (CBx) inhibit these CRAC channels and thereby suppress signal transduction through the Calmodulin (CaM) - Calcineurin (CaN) - Nuclear Factor of Activated T cells (NFAT) pathway, which regulates cytokine release and cell proliferation.
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影响因子：
4.7
作者：
Borrelli, Francesca;Pagano, Ester;Izzo, Angelo A.
通讯作者：
Izzo, Angelo A.
影响因子：
16
作者：
Kar, Pulak;Mirams, Gary R.;Christian, Helen C.;Parekh, Anant B.
通讯作者：
Parekh, Anant B.
影响因子：
5.6
作者：
Berlansky S;Humer C;Sallinger M;Frischauf I
通讯作者：
Frischauf I
影响因子：
64.8
作者：
HOTH, M;PENNER, R
通讯作者：
PENNER, R
影响因子：
5
作者：
Ben-Shabat, S;Fride, E;Mechoulam, R
通讯作者：
Mechoulam, R