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WZ3146 inhibits mast cell Lyn and Fyn to reduce IgE-mediated allergic responses in vitro and in vivo.
Toxicology and Applied Pharmacology ( IF 3.3 ) Pub Date : 2019-09-14 , DOI: 10.1016/j.taap.2019.114763
Young Hwan Park 1 , Do Kyun Kim 1 , Hyuk Soon Kim 1 , Dajeong Lee 1 , Min Bum Lee 1 , Keun Young Min 1 , Min Geun Jo 1 , Ji Eon Lee 1 , Young Mi Kim 2 , Wahn Soo Choi 1
Affiliation  

Mast cells (MCs) play an important role as effector cells that cause allergic responses in allergic diseases. For these reasons, MC is considered an attractive therapeutic target for allergic disease treatment. In this study, we investigated the inhibitory effect of WZ3146, N-[3-[5-chloro-2-[4-(4-methylpiperazin-1-yl)anilino]pyrimidin-4-yl]oxyphenyl]prop-2-enamide, and the mechanisms of its actions on the MC activation and IgE-mediated allergic response by using three types of MCs such as rat basophilic leukemia (RBL)-2H3 cells, mouse bone marrow mast cells (BMMCs), and human Laboratory of Allergic Diseases 2 (LAD2) cells. WZ3146 inhibited antigen-stimulated degranulation in a dose-dependent manner (IC50, ~ 0.35 μM for RBL-2H3 cells; ~ 0.39 μM for BMMCs; ~ 0.41 for LAD2 cells). WZ3146 also suppressed the production of histamine, tumor necrosis factor (TNF)-α and interleukin (IL)-6, which mediate various allergic responses, in a dose-dependent manner. As the mechanism of WZ3146 to inhibit MCs, it inhibited the activation of spleen tyrosine kinase (Syk) and the downstream signaling proteins of Syk such as linker for activation of T cell (LAT) and phospholipase (PL) Cγ1 in the signaling pathway of FcεRI. In addition, WZ3146 inhibited the activation of Akt, extracellular signal-regulated kinase (ERK)1/2, p38, and c-Jun N-terminal kinase (JNK). However, WZ3146 did not inhibit degranulation of MCs by thapsigargin or ionomycin, which increase calcium concentration in cytosol. Notably, WZ3146 inhibited the activity of Lyn and Fyn, but not Syk. In an following animal experiment, WZ3146 inhibited IgE-dependent passive cutaneous anaphylaxis (PCA) in a dose-dependent manner (ED50, ~ 20 mg/kg). Taken together, in this study we show that the pyrimidine derivative, WZ3146, inhibits the IgE-mediated allergic response by inhibiting Lyn and Fyn Src-family kinases, which are initially activated by antigen stimulation in MCs. Therefore, we propose that WZ3146 could be used as a new therapeutic agent for the treatment of allergic diseases.

中文翻译:

WZ3146在体外和体内抑制肥大细胞Lyn和Fyn,以减少IgE介导的过敏反应。

肥大细胞(MC)作为效应细胞,在过敏性疾病中引起过敏反应,起着重要的作用。由于这些原因,MC被认为是变应性疾病治疗的有吸引力的治疗靶标。在这项研究中,我们研究了WZ3146,N- [3- [5-氯-2- [4-(4-甲基哌嗪-1-基)苯胺基]嘧啶-4-基]氧苯基]丙-2-的抑制作用。酰胺,及其对MC活化和IgE介导的过敏反应的作用机理,使用三种类型的MC,例如大鼠嗜碱性白血病(RBL)-2H3细胞,小鼠骨髓肥大细胞(BMMC)和人体过敏实验室疾病2(LAD2)细胞。WZ3146以剂量依赖性方式抑制抗原刺激的脱粒(IC50,对于RBL-2H3细胞为〜0.35μM;对于BMMC为〜0.39μM;对于LAD2细胞为〜0.41)。WZ3146还抑制了组胺的产生,肿瘤坏死因子(TNF)-α和白介素(IL)-6,以剂量依赖的方式介导各种变态反应。作为WZ3146抑制MC的机制,它抑制脾酪氨酸激酶(Syk)和Syk下游信号蛋白的活化,例如FcεRI信号通路中T细胞(LAT)和磷脂酶(PL)Cγ1激活的连接子。 。此外,WZ3146抑制了Akt,细胞外信号调节激酶(ERK)1/2,p38和c-Jun N端激酶(JNK)的激活。但是,WZ3146不能抑制毒胡萝卜素或离子霉素对MC的脱颗粒作用,后者可增加细胞溶质中的钙浓度。值得注意的是,WZ3146抑制Lyn和Fyn的活性,但不抑制Syk的活性。在随后的动物实验中,WZ3146以剂量依赖的方式抑制了IgE依赖的被动皮肤过敏反应(PCA)(ED50,〜20 mg / kg)。两者合计,在这项研究中,我们表明嘧啶衍生物WZ3146通过抑制Lyn抗原和Fyn Src家族激酶(最初由MC中的抗原刺激激活)来抑制IgE介导的过敏反应。因此,我们建议将WZ3146用作治疗过敏性疾病的新型治疗剂。
更新日期:2019-09-16
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