dTBP2通过阻断dTCTP介导的细胞炎症网络减轻严重的气道炎症
2021/11/24
摘要
背景：翻译调控的二聚体肿瘤蛋白(dTCTP)，又称组胺释放因子，可增强过敏反应，其在过敏性哮喘等炎症性疾病中表达增加。尽管dTCTP在过敏性炎症中发挥重要作用，但其产生途径、相关细胞网络和潜在分子机制却知之甚少。
目的：在本研究中，我们探讨了dTCTP介导的炎症网络及其与脂多糖(LPS)相关的分子机制。
结果：LPS刺激增加了肥大细胞产生dTCTP和脱颗粒过程中dTCTP的分泌，细胞外dTCTP随后增加了气道上皮细胞产生的促炎分子，包括IL-8，而不影响肥大细胞的活化。此外，二聚 TCTP 结合肽 2 (dTBP2)，一种 dTCTP 抑制剂肽，选择性地阻断了 dTCTP 介导的从肥大细胞到上皮细胞的信号网络，并通过气道上皮细胞中的 IkB 诱导和核 p65 外迁减少了 IL-8 的产生。更重要的是，dTBP2在体内有效减弱脂多糖诱导的严重气道炎症，降低免疫细胞浸润和IL-17的产生，并减弱dTCTP的分泌。
结论：这些结果表明，肥大细胞产生的dTCTP通过旁分泌信号途径激活气道上皮细胞，从而加剧气道炎症，而dTBP2通过阻断dTCTP介导的炎症细胞网络，有利于严重气道炎症的治疗。
dTBP2 attenuates severe airway inflammation by blocking inflammatory cellular network mediated by dTCTP
J Cho H, Kim HK, Oh A, et al.
Abstract
BACKGROUND: Dimeric translationally controlled tumor protein (dTCTP), also known as histamine-releasing factor, amplifies allergic responses and its production has been shown to increase in inflammatory diseases such as allergic asthma. Despite the critical role of dTCTP in allergic inflammation, little is known about its production pathways, associated cellular networks, and underlying molecular mechanisms.
OBJECTIVE:In this study, we explored the dTCTP mediated inflammatory networks and molecular mechanisms of dTCTP associated with lipopolysaccharides (LPS)-induced severe asthma.
RESULTS:LPS stimulation increased dTCTP production by mast cells and dTCTP secretion during degranulation, and extracellular dTCTP subsequently increased the production of pro-inflammatory molecules, including IL-8, by airway epithelial cells without affecting mast cell activation. Furthermore, dimeric TCTP-binding peptide 2 (dTBP2), a dTCTP inhibitor peptide, selectively blocked the dTCTP-mediated signaling network from mast cells to epithelial cells and decreased IL-8 production through IkB induction and nuclear p65 export in airway epithelial cells. More importantly, dTBP2 efficiently attenuated LPS-induced severe airway inflammation in vivo, resulting in decreased immune cell infiltration and IL-17 production and attenuated dTCTP secretion.
CONCLUSIONS: These results suggest that dTCTP produced by mast cells exacerbates airway inflammation through activation of airway epithelial cells in a paracrine signaling manner, and that dTBP2 is beneficial in the treatment of severe airway inflammation by blocking the dTCTP-mediated inflammatory cellular network.
背景：翻译调控的二聚体肿瘤蛋白(dTCTP)，又称组胺释放因子，可增强过敏反应，其在过敏性哮喘等炎症性疾病中表达增加。尽管dTCTP在过敏性炎症中发挥重要作用，但其产生途径、相关细胞网络和潜在分子机制却知之甚少。
目的：在本研究中，我们探讨了dTCTP介导的炎症网络及其与脂多糖(LPS)相关的分子机制。
结果：LPS刺激增加了肥大细胞产生dTCTP和脱颗粒过程中dTCTP的分泌，细胞外dTCTP随后增加了气道上皮细胞产生的促炎分子，包括IL-8，而不影响肥大细胞的活化。此外，二聚 TCTP 结合肽 2 (dTBP2)，一种 dTCTP 抑制剂肽，选择性地阻断了 dTCTP 介导的从肥大细胞到上皮细胞的信号网络，并通过气道上皮细胞中的 IkB 诱导和核 p65 外迁减少了 IL-8 的产生。更重要的是，dTBP2在体内有效减弱脂多糖诱导的严重气道炎症，降低免疫细胞浸润和IL-17的产生，并减弱dTCTP的分泌。
结论：这些结果表明，肥大细胞产生的dTCTP通过旁分泌信号途径激活气道上皮细胞，从而加剧气道炎症，而dTBP2通过阻断dTCTP介导的炎症细胞网络，有利于严重气道炎症的治疗。
（中日友好医院呼吸与危重症医学科 李春晓 摘译 林江涛 审校）
（Biomed Pharmacother, 2021, 144: 112316.）
（Biomed Pharmacother, 2021, 144: 112316.）
dTBP2 attenuates severe airway inflammation by blocking inflammatory cellular network mediated by dTCTP
J Cho H, Kim HK, Oh A, et al.
Abstract
BACKGROUND: Dimeric translationally controlled tumor protein (dTCTP), also known as histamine-releasing factor, amplifies allergic responses and its production has been shown to increase in inflammatory diseases such as allergic asthma. Despite the critical role of dTCTP in allergic inflammation, little is known about its production pathways, associated cellular networks, and underlying molecular mechanisms.
OBJECTIVE:In this study, we explored the dTCTP mediated inflammatory networks and molecular mechanisms of dTCTP associated with lipopolysaccharides (LPS)-induced severe asthma.
RESULTS:LPS stimulation increased dTCTP production by mast cells and dTCTP secretion during degranulation, and extracellular dTCTP subsequently increased the production of pro-inflammatory molecules, including IL-8, by airway epithelial cells without affecting mast cell activation. Furthermore, dimeric TCTP-binding peptide 2 (dTBP2), a dTCTP inhibitor peptide, selectively blocked the dTCTP-mediated signaling network from mast cells to epithelial cells and decreased IL-8 production through IkB induction and nuclear p65 export in airway epithelial cells. More importantly, dTBP2 efficiently attenuated LPS-induced severe airway inflammation in vivo, resulting in decreased immune cell infiltration and IL-17 production and attenuated dTCTP secretion.
CONCLUSIONS: These results suggest that dTCTP produced by mast cells exacerbates airway inflammation through activation of airway epithelial cells in a paracrine signaling manner, and that dTBP2 is beneficial in the treatment of severe airway inflammation by blocking the dTCTP-mediated inflammatory cellular network.
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