Glaucocalyxin A Attenuates Allergic Responses by Inhibiting Mast Cell Degranulation through p38MAPK/NrF2/HO-1 and HMGB1/TLR4/NF-κB Signaling Pathways.
Glaucocalyxin A Attenuates Allergic Responses by Inhibiting Mast Cell Degranulation through p38MAPK/NrF2/HO-1 and HMGB1/TLR4/NF-κB Signaling Pathways.
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DOI：
10.1155/2021/6644751
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Yan G
中科院分区：
文献类型：
--
作者：
Piao Y;Jiang J;Wang Z;Wang C;Jin S;Li L;Li L;Piao H;Jin Z;Zhu L;Yan G
蓝萼甲素（Glaucocalyxin A，GLA）具有抗氧化、免疫调节、抗动脉粥样硬化等多种药理作用。本研究旨在探讨GLA对肥大细胞脱颗粒的影响及其机制。抗DNP IgE介导的被动皮肤过敏反应（PCA）的结果表明，GLA显着抑制PCA在体内，证明了减少伊文思蓝外渗和减少耳朵厚度。此外，GLA在体外显著减少RBL-2 H3（大鼠嗜碱性白血病细胞）和RPMC（腹膜肥大细胞）中组胺和β-氨基己糖苷酶的释放、钙内流、细胞因子（IL-4、TNF-α、IL-1β、IL-13和IL-8）的产生。此外，我们还通过Western blot进一步研究了GLA对抗原诱导的肥大细胞的调节机制，结果表明GLA抑制Fcε RI介导的信号转导，使Syk、Fyn、林恩、Gab 2和PLC-γ1的磷酸化失效。此外，GLA通过限制NF-κ Bp 65的核转位，抑制重组小鼠高迁移率族蛋白B1-（HMGB 1-）诱导的肥大细胞脱颗粒。用siRNA-HMGB 1处理肥大细胞显著抑制HMGB 1水平以及MyD 88和TLR 4，降低细胞内钙水平，并抑制β-氨基己糖苷酶的释放。同时，GLA通过激活p38 MAPK磷酸化而增加NrF 2和HO-1的表达。提示GLA通过p38 MAPK磷酸化调节NrF 2/HO-1信号通路，抑制HMGB 1/TLR 4/NF-κB信号通路，减轻肥大细胞脱颗粒和过敏性炎症。我们的研究结果可作为一个有前途的治疗药物，对过敏性炎症性疾病。
Glaucocalyxin A (GLA) has various pharmacological effects like antioxidation, immune regulation, and antiatherosclerosis. Here, in this study, the effect and mechanism of GLA on mast cell degranulation were studied. The results of the anti-DNP IgE-mediated passive cutaneous anaphylaxis (PCA) showed that GLA dramatically inhibited PCA in vivo, as evidenced by reduced Evans blue extravasation and decreased ear thickness. In addition, GLA significantly reduced the release of histamine and β-hexosaminidase, calcium influx, cytokine (IL-4, TNF-α, IL-1β, IL-13, and IL-8) production in the RBL-2H3 (rat basophilic leukemia cells), and RPMCs (peritoneal mast cells) in vitro. Moreover, we further investigated the regulatory mechanism of GLA on antigen-induced mast cells by Western blot, which showed that GLA inhibited FcεRI-mediated signal transduction and invalidated the phosphorylation of Syk, Fyn, Lyn, Gab2, and PLC-γ1. In addition, GLA inhibited the recombinant mouse high mobility group protein B1- (HMGB1-) induced mast cell degranulation through limiting nuclear translocation of NF-κBp65. Treatment of mast cells with siRNA-HMGB1 significantly inhibited HMGB1 levels, as well as MyD88 and TLR4, decreased intracellular calcium levels, and suppressed the release of β-hexosaminidase. Meanwhile, GLA increased NrF2 and HO-1 levels by activating p38MAPK phosphorylation. Consequently, these data suggest that GLA regulates the NrF2/HO-1 signaling pathway through p38MAPK phosphorylation and inhibits HMGB1/TLR4/NF-κB signaling pathway to reduce mast cell degranulation and allergic inflammation. Our findings could be used as a promising therapeutic drug against allergic inflammatory disease.
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