Key Laboratory of Gene Engineering of the Ministry of Education, Guangdong Key Laboratory of Plant Resources, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, PR China.
Eur J Pharmacol. 2012 Sep 5;690(1-3):207-13. doi: 10.1016/j.ejphar.2012.06.040. Epub 2012 Jul 2.
Naringenin, the aglycone of naringin, has been reported to attenuate MUC5AC secretion by inhibiting activity of nuclear factor kappa B (NF-κB) via EGFR-PI3K-Akt/ERK MAPKinase signaling pathways. However, previous studies demonstrated that the MUC5AC promoter was located in two different regions: an activator protein-1 (AP-1) binding site and a NF-κB binding site. The current study comprehensively determined the involvement of MAPKs/AP-1 and IKKs/IκB/NF-κB in epidermal growth factor (EGF)-induced A549 cells, and sought to ascertain the signaling pathways of naringin imparted in suppression of EGF-induced MUC5AC secretion. The results showed that naringin of 100 μM not only significantly decreased EGF-induced overexpressions of both MUC5AC mucin and mRNA in A549 cells, but also suppressed the phosphorylation of EGF receptor, p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK1/2), and c-Jun N-terminal kinase (JNK), as well as nucleus NF-κB p65 and AP-1. Moreover, any of three MAPKs inhibitors (PD98059, SB203580, and SP600125) significantly inhibited EGF-induced MUC5AC secretion. And as compared to MG132, the inhibitor κB (IκB) phosphorylation inhibitor of SN50 was more effective in reducing EGF-induced MUC5AC secretion because of suppression of nucleus AP-1. Meanwhile, as compared to naringin, both SP600125 and azithromycin were less effective in suppressing EGF-induced secretion of MUC5AC because of the unchanged nucleus NF-κB p65. These results indicated that naringin attenuates EGF-induced MUC5AC secretion in A549 cells by suppressing the cooperative activities of MAPKs/AP-1 and IKKs/IκB/NF-κB signaling pathways.
柚皮苷是柚皮苷的配糖体，据报道，通过 EGFR-PI3K-Akt/ERK MAPKinase 信号通路抑制核因子 kappa B (NF-κB) 的活性，可减轻 MUC5AC 的分泌。然而，先前的研究表明，MUC5AC 启动子位于两个不同的区域：激活蛋白-1 (AP-1) 结合位点和 NF-κB 结合位点。本研究全面确定了 MAPKs/AP-1 和 IKKs/IκB/NF-κB 在表皮生长因子 (EGF) 诱导的 A549 细胞中的参与情况，并试图确定柚皮苷在抑制 EGF 诱导的 MUC5AC 分泌中所赋予的信号通路。结果表明，100 μM 的柚皮苷不仅显著降低了 EGF 诱导的 A549 细胞中 MUC5AC 粘蛋白和 mRNA 的过度表达，还抑制了 EGF 受体、p38 丝裂原活化蛋白激酶 (MAPK)、细胞外信号调节激酶 (ERK1/2) 和 c-Jun N-末端激酶 (JNK) 的磷酸化，以及核 NF-κB p65 和 AP-1。此外，三种 MAPK 抑制剂 (PD98059、SB203580 和 SP600125) 中的任何一种都能显著抑制 EGF 诱导的 MUC5AC 分泌。与 MG132 相比，SN50 的 IκB 磷酸化抑制剂对 NF-κB 的抑制作用更强，因此更能有效减少 EGF 诱导的 MUC5AC 分泌。同时，与柚皮苷相比，SP600125 和阿奇霉素抑制 EGF 诱导的 MUC5AC 分泌的效果较差，因为核 NF-κB p65 不变。这些结果表明，柚皮苷通过抑制 MAPKs/AP-1 和 IKKs/IκB/NF-κB 信号通路的协同活性，减轻 EGF 诱导的 A549 细胞中 MUC5AC 的分泌。
