Pig Liver Esterases Hydrolyze Endocannabinoids and Promote Inflammatory Response.
Pig Liver Esterases Hydrolyze Endocannabinoids and Promote Inflammatory Response.
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猪肝酯酶水解内源性大麻素并促进炎症反应
DOI：
10.3389/fimmu.2021.670427
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发表时间：
2021
影响因子：
7.3
通讯作者：
Shi D
中科院分区：
文献类型：
--
作者：
Zhou Q;Yan B;Sun W;Chen Q;Xiao Q;Xiao Y;Wang X;Shi D
内源性大麻素是大麻素受体的内源性配体，激活这些受体具有很强的生理和病理意义。在结构上，内源性大麻素是酯(例如，2-花生四烯基甘油，2-AG)或酰胺(例如，N-花生四烯基乙醇胺，AEA)。这些化合物的水解产生花生四烯酸(AA)，这是前列腺素E2等促炎介质的主要前体。羧酸酯酶是已知的高效水解酯和酰胺的酶。CES1是一种人的羧酸酯酶，具有2-AG水解酶活性，与猪羧酸酯酶PLE1和PLE6(猪肝酯酶)有很高的同源性。本研究旨在验证PLE1和PLE6对内源性大麻素的降解和促进炎症反应的假说。与假设一致，纯化的PLE1和PLE6能有效地降解2-AG和AEA。PLE6对2-AG和AEA的活性分别是PLE1的40倍和3倍。此外，PLE1和PLE6对双(4-硝基苯基)磷酸(BNPP)高度敏感，BNPP是一种已知主要抑制羧酸酯酶的芳基磷酸二酯。根据与BNPP的研究，PLES对不同器官和细胞中2-AG的水解率为53.4-88.4%。关键的是，外源性PLE6的加入或转染增加了促炎症细胞因子的表达和分泌，以响应免疫刺激剂脂多糖(LPS)。这种增加在共培养的肺泡巨噬细胞和跨孔中的PLE6转基因细胞中得到重现。最后，BNPP减轻了由内毒素引发的炎症，同时减少了AA和促炎介质的形成。这些发现定义了一种创新的联系：肺-内源性大麻素-炎症。这种机械性的联系表明，羧酸酯酶在与内源性大麻素代谢相关的病理生理过程中起着关键作用。
Endocannabinoids are endogenous ligands of cannabinoid receptors and activation of these receptors has strong physiological and pathological significance. Structurally, endocannabinoids are esters (e.g., 2-arachidonoylglycerol, 2-AG) or amides (e.g., N-arachidonoylethanolamine, AEA). Hydrolysis of these compounds yields arachidonic acid (AA), a major precursor of proinflammatory mediators such as prostaglandin E2. Carboxylesterases are known to hydrolyze esters and amides with high efficiency. CES1, a human carboxylesterase, has been shown to hydrolyze 2-AG, and shares a high sequence identity with pig carboxylesterases: PLE1 and PLE6 (pig liver esterase). The present study was designed to test the hypothesis that PLE1 and PLE6 hydrolyze endocannabinoids and promote inflammatory response. Consistent with the hypothesis, purified PLE1 and PLE6 efficaciously hydrolyzed 2-AG and AEA. PLE6 was 40-fold and 3-fold as active as PLE1 towards 2-AG and AEA, respectively. In addition, both PLE1 and PLE6 were highly sensitive to bis(4-nitrophenyl) phosphate (BNPP), an aryl phosphodiester known to predominately inhibit carboxylesterases. Based on the study with BNPP, PLEs contributed to the hydrolysis of 2-AG by 53.4 to 88.4% among various organs and cells. Critically, exogenous addition or transfection of PLE6 increased the expression and secretion of proinflammatory cytokines in response to the immunostimulant lipopolysaccharide (LPS). This increase was recapitulated in cocultured alveolar macrophages and PLE6 transfected cells in transwells. Finally, BNPP reduced inflammation trigged by LPS accompanied by reduced formation of AA and proinflammatory mediators. These findings define an innovative connection: PLE-endocannabinoid-inflammation. This mechanistic connection signifies critical roles of carboxylesterases in pathophysiological processes related to the metabolism of endocannabinoids.
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DOI：
10.1016/j.bbalip.2016.03.003
发表时间：
2016-06
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Leishman E;Mackie K;Luquet S;Bradshaw HB
通讯作者：
Bradshaw HB
DOI：
10.1515/bchm2.1967.348.1.609
发表时间：
1967-01-01
影响因子：
--
作者：
HEYMANN, E;KRISCH, K
通讯作者：
KRISCH, K
影响因子：
5.1
作者：
Lenfant, Nicolas;Bourne, Yves;Chatonnet, Arnaud
通讯作者：
Chatonnet, Arnaud
影响因子：
4.1
作者：
MENTLEIN, R;BERGE, RK;HEYMANN, E
通讯作者：
HEYMANN, E
影响因子：
2.1
作者：
Hosokawa, Masakiyo;Furihata, Tomomi;Chiba, Kan
通讯作者：
Chiba, Kan