CDK4/6 inhibitor palbociclib suppresses IgE-mediated mast cell activation
CDK4/6 inhibitor palbociclib suppresses IgE-mediated mast cell activation
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CDK4/6 抑制剂 palbociclib 抑制 IgE 介导的肥大细胞激活
DOI：
10.1186/s12967-019-2026-9
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发表时间：
2019-08-20
影响因子：
7.4
通讯作者：
Chen, Jia-Jie
中科院分区：
文献类型：
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作者：
Hou, Yi-Bo;Ji, Kunmei;Chen, Jia-Jie
背景肥大细胞活化可引起脱颗粒和细胞因子的释放，从而促进炎症。方法用抗二硝基酚(DNP)免疫球蛋白(Ig)E抗体致敏RBL-2H3大鼠嗜碱粒细胞(BLCs)和小鼠骨髓肥大细胞(BMMCs)，用DNP-人血清白蛋白(HSA)抗原刺激肥大细胞，再用CDK4/6抑制剂palbociclib处理。应用组织学染色观察细胞形态变化。采用小鼠IgE介导的被动皮肤过敏反应(PCA)和卵清蛋白(OVA)诱导的主动全身过敏反应(ASA)模型，观察帕波西利对体内变态反应的影响。结果活化的BLCs和BMMC释放丰富的颗粒相关介质(组胺和β-氨基己糖苷酶)，并被PABOICLIB浓度依赖地降低。Palbociclib抑制活化的BLC中肥大细胞激活标记CD63的表达，抑制颗粒释放(甲苯胺蓝染色)，同时阻止形态改变(延长的形状保持)和丝状肌动蛋白(F-肌动蛋白)重组。Palbociclib抑制刺激的BLCs中与肥大细胞激活相关的分子Lyn和/或丝裂原活化蛋白激酶(MAPK)信号，并减轻PCA小鼠的过敏反应，呈剂量依赖关系。结论在体内外，Palbociclib均可抑制IgE介导的肥大细胞活化，提示其可能通过抑制肥大细胞脱颗粒而成为治疗肥大细胞介导的变态反应性疾病的药物。
BackgroundMast cell activation causes degranulation and release of cytokines, thereby promoting inflammation. The aim of this study was to investigate the inhibitory effect of CDK4/6 inhibition on mast cell activation in vitro and in vivo.MethodsRBL-2H3 rat basophilic leukemia cells (BLCs) and mouse bone marrow-derived mast cells (BMMCs) were sensitized with anti-dinitrophenol (DNP) immunoglobulin (Ig)E antibodies, stimulated with DNP-human serum albumin (HSA) antigens, and treated with the CDK4/6 inhibitor palbociclib. Histological stains were applied to reveal cytomorphological changes. Murine IgE-mediated passive cutaneous anaphylaxis (PCA) and ovalbumin (OVA)-induced active systemic anaphylaxis (ASA) models were used to examine palbociclib effects on allergic reactions in vivo. Western blots were performed to detect the expression of cell signaling molecules associated with mast cell activation.ResultsActivated BLCs and BMMCs released copious granule-related mediators (histamine and β-hexosaminidase), which was reduced by palbociclib in a concentration-dependent manner. Palbociclib inhibited expression of the mast cell activation marker CD63 in activated BLCs and inhibited granule release (visualized with toluidine blue staining) while preventing morphological changes, (elongated shape maintained) and filamentous actin (F-actin) reorganization. Palbociclib suppressed molecular Lyn and/or mitogen-activated protein kinase (MAPK) signaling associated with mast cell activation in stimulated BLCs and attenuated allergic reactions in PCA mice dose dependently. Palbociclib attenuated body temperature reduction and diminished serum histamine levels in ovalbumin OVA-challenged ASA mice.ConclusionPalbociclib suppresses IgE-mediated mast cell activation in vitro and in vivo, suggesting that it may be developed into a therapy for mast cell-mediated allergic diseases via inhibition of mast cell degranulation.