College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of Korea.
Department of Pharmacology, School of Medicine, Daegu Catholic University, Daegu 42472, Republic of Korea.
Cells. 2023 Feb 1;12(3):469. doi: 10.3390/cells12030469.
Allergy is a chronic inflammatory disease, and its incidence has increased worldwide in recent years. Thalidomide, which was initially used as an anti-emetic drug but was withdrawn due to its teratogenic effects, is now used to treat blood cancers. Although the anti-inflammatory and immunomodulatory properties of thalidomide have been reported, little is known about its influence on the mast cell-mediated allergic reaction. In the present study, we aimed to evaluate the anti-allergic activity of thalidomide and the underlying mechanism using mouse bone marrow-derived mast cells (BMMCs) and passive cutaneous anaphylaxis (PCA) mouse models. Thalidomide markedly decreased the degranulation and release of lipid mediators and cytokines in IgE/Ag-stimulated BMMCs, with concurrent inhibition of FcεRI-mediated positive signaling pathways including Syk and activation of negative signaling pathways including AMP-activated protein kinase (AMPK) and SH2 tyrosine phosphatase-1 (SHP-1). The knockdown of AMPK or SHP-1 with specific siRNA diminished the inhibitory effects of thalidomide on BMMC activation. By contrast, the knockdown of cereblon (CRBN), which is the primary target protein of thalidomide, augmented the effects of thalidomide. Thalidomide reduced the interactions of CRBN with Syk and AMPK promoted by FcεRI crosslinking, thereby relieving the suppression of AMPK signaling and suppressing Syk signaling. Furthermore, oral thalidomide treatment suppressed the PCA reaction in mice. In conclusion, thalidomide suppresses FcεRI-mediated mast cell activation by activating the AMPK and SHP-1 pathways and antagonizing the action of CRBN, indicating that it is a potential anti-allergic agent.
过敏是一种慢性炎症性疾病，近年来在全球范围内的发病率有所增加。沙利度胺最初被用作止吐药，但因其致畸作用而被撤出市场，现在被用于治疗血液癌。尽管已经报道了沙利度胺的抗炎和免疫调节特性，但对其对肥大细胞介导的过敏反应的影响知之甚少。在本研究中，我们旨在使用鼠骨髓来源的肥大细胞（BMMC）和被动皮肤过敏（PCA）小鼠模型评估沙利度胺的抗过敏活性及其潜在机制。沙利度胺显著降低了 IgE/Ag 刺激的 BMMC 脱颗粒和脂质介质及细胞因子的释放，同时抑制了 FcεRI 介导的包括 Syk 在内的正向信号通路，并激活了包括 AMP 激活的蛋白激酶（AMPK）和 SH2 酪氨酸磷酸酶-1（SHP-1）在内的负向信号通路。用特异性 siRNA 敲低 AMPK 或 SHP-1 可减弱沙利度胺对 BMMC 激活的抑制作用。相比之下，用沙利度胺的主要靶蛋白 cereblon（CRBN）的特异性 siRNA 敲低则增强了沙利度胺的作用。沙利度胺减少了 FcεRI 交联促进的 CRBN 与 Syk 和 AMPK 的相互作用，从而缓解了 AMPK 信号的抑制和 Syk 信号的抑制。此外，口服沙利度胺治疗可抑制小鼠的 PCA 反应。总之，沙利度胺通过激活 AMPK 和 SHP-1 通路并拮抗 CRBN 的作用来抑制 FcεRI 介导的肥大细胞激活，表明它是一种有潜力的抗过敏药物。
