Background: Hippo-Yes-associated protein (YAP) pathway plays an important role in epithelial cell proliferation and inflammation development in chronic rhinosinusitis with nasal polyps (CRSwNP). However, the underlying mechanisms remain unclear.
Objective: This study intends to investigate the role of YAP and the nuclear factor kappa-B (NF-κB) pathway in cell proliferation and the expression of epithelium-derived cytokines in nasal polyps (NP).
Methods: The expression levels of YAP, TEA domain family member 1 (TEAD1), Ki-67, and NF-κB as well as interleukin (IL-) 33, IL-25 and thymic stromal lymphopoietin (TSLP) in sinonasal mucosa, primary nasal epithelial cells (NPECs), and human nasal epithelial RPMI 2650 cells were detected. NPECs were cultured and treated with verteporfin (VP), YAP shRNA or BAY 11– 7082.
Results: The hippo pathway effector YAP, Ki-67, p65 NF-κB, and cyclin D1 were significantly increased in NP compared with control mucosa, which was accompanied by overexpression of IL-33, IL-25, and TSLP. Pharmaceutical inhibition of YAP by VP suppressed cell proliferation of RPMI 2650 cells by blocking cell cycle progression at G0/G1 without inducing obvious cell apoptosis. Furthermore, lentiviral transfection-mediated knockdown of hippo pathway activity reduced the expression of IL-33, IL-25, TSLP as well as p65 NF-κB in RPMI 2650 cells. Downregulation of NF-κB pathway with BAY 11– 7082 in NPECs could decrease the mRNA level of TSLP, IL-33 and IL-25 accordingly.
Conclusion: Inhibition of hippo pathway suppressed nasal epithelial cell proliferation and declined the expression of epithelium-derived cytokines via the NF-κB pathway in NPECs.



中文翻译：

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YAP 通过鼻息肉中的 NF-κB 通路促进细胞增殖和上皮细胞因子表达

背景： Hippo-Yes 相关蛋白 (YAP) 通路在慢性鼻窦炎鼻息肉 (CRSwNP) 的上皮细胞增殖和炎症发展中起重要作用。然而，潜在的机制仍不清楚。
目的：本研究旨在探讨 YAP 和核因子 kappa-B (NF-κB) 通路在鼻息肉 (NP) 细胞增殖和上皮衍生细胞因子表达中的作用。
方法：YAP、TEA 域家族成员 1 (TEAD1)、Ki-67 和 NF-κB 以及白细胞介素 (IL-) 33、IL-25 和胸腺基质淋巴细胞生成素 (TSLP) 在鼻窦黏膜、原发性鼻上皮中的表达水平细胞 (NPECs) 和人鼻上皮 RPMI 2650 细胞被检测到。NPECs 被培养并用维替泊芬 (VP)、YAP shRNA 或 BAY 11-7082 处理。
结果：与对照粘膜相比，NP 中河马通路效应子 YAP、Ki-67、p65 NF-κB 和细胞周期蛋白 D1 显着增加，并伴有 IL-33、IL-25 和 TSLP 的过表达。VP 对 YAP 的药物抑制通过阻断 G0/G1 的细胞周期进程来抑制 RPMI 2650 细胞的细胞增殖，而不会诱导明显的细胞凋亡。此外，慢病毒转染介导的河马通路活性敲低降低了 RPMI 2650 细胞中 IL-33、IL-25、TSLP 以及 p65 NF-κB 的表达。在NPECs中用BAY 11-7082下调NF-κB通路可以相应地降低TSLP、IL-33和IL-25的mRNA水平。
结论： 抑制河马通路可抑制鼻上皮细胞增殖，并通过 NPEC 中的 NF-κB 通路降低上皮衍生细胞因子的表达。