Cho Hyunsoo, Park Jiyoung, Kim Hyo Kyeong, Hwang Eun Sook, Lee Kyunglim
Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, South Korea.
Fluorescence Core Imaging Center, Department of Life Science, Ewha Womans University, Seoul, South Korea.
Front Pharmacol. 2021 Oct 19;12:764321. doi: 10.3389/fphar.2021.764321. eCollection 2021.
Dimerized translationally controlled tumor protein (dTCTP) amplifies allergic responses through activation of several types of immune cells and release of inflammatory mediators. In particular, dTCTP plays an important role in histamine release by triggering mast cells and has been proposed as a target in the treatment of allergic diseases. dTCTP-binding peptide 2 (dTBP2) is known to attenuate severe allergic rhinitis and asthma through inhibition of dTCTP activity on airway epithelial cells and T cells; however, it is unclear whether dTBP2 affects mast cell function and mast cell disease. In this study, we explored the effects of dTBP2 on mast cell degranulation and allergen-induced anaphylactic reactions. We found that bacterial product lipopolysaccharide increased the expression of dTCTP in mast cells and rapidly released dTCTP by the mast cell stimulator compound 48/80. Interestingly, the released dTCTP further promoted mast cell degranulation in an autocrine activation manner and increased calcium mobilization in mast cells, which is essential for degranulation. Furthermore, dTBP2 directly and dose-dependently inhibited mast cell degranulation enhanced by compound 48/80, suggesting a direct and potent anti-anaphylactic activity of dTBP2. dTBP2 also significantly suppressed the dTCTP-induced degranulation and histamine release through inhibition of the p38 MAPK signaling pathway and suppression of lysosomal expansion and calcium mobilization in mast cells. More importantly, administration of dTBP2 decreased mortality and significantly attenuated histamine release and inflammatory cytokine production in compound 48/80-induced systemic anaphylactic reactions. These results suggest that dTBP2 is beneficial for the control of anaphylaxis with increased dTCTP.
二聚化的翻译调控肿瘤蛋白（dTCTP）通过激活多种免疫细胞并释放炎症介质来放大过敏反应。特别是，dTCTP通过触发肥大细胞在组胺释放中起重要作用，并已被提议作为过敏性疾病治疗的靶点。已知dTCTP结合肽2（dTBP2）通过抑制dTCTP对气道上皮细胞和T细胞的活性来减轻严重的过敏性鼻炎和哮喘；然而，尚不清楚dTBP2是否影响肥大细胞功能和肥大细胞疾病。在本研究中，我们探讨了dTBP2对肥大细胞脱颗粒和过敏原诱导的过敏反应的影响。我们发现细菌产物脂多糖增加了肥大细胞中dTCTP的表达，并通过肥大细胞刺激剂化合物48/80快速释放dTCTP。有趣的是，释放的dTCTP以自分泌激活方式进一步促进肥大细胞脱颗粒，并增加肥大细胞中的钙动员，这对脱颗粒至关重要。此外，dTBP2直接且剂量依赖性地抑制由化合物48/80增强的肥大细胞脱颗粒，表明dTBP2具有直接且有效的抗过敏活性。dTBP2还通过抑制p38 MAPK信号通路以及抑制肥大细胞中的溶酶体扩张和钙动员，显著抑制dTCTP诱导的脱颗粒和组胺释放。更重要的是，给予dTBP2可降低死亡率，并显著减轻化合物48/80诱导的全身过敏反应中的组胺释放和炎症细胞因子产生。这些结果表明，dTBP2有助于控制dTCTP增加时的过敏反应。
