Interleukin-5 (IL-5) strongly initiates the asthmatic inflammatory response, which affects 300 million patients with asthma annually worldwide, through oxidative stress generation. Citrus flavonoids have beneficial properties, such as anti-inflammatory and antioxidant properties, but the precise molecular mechanism of the inhibition of the asthmatic inflammatory response is still unclear. This study aimed to investigate the underlying mechanisms of ROS and IL-5 reduction with citrus flavonoid treatment in PMA/ionomycin-induced EL-4 cells. Our results showed that hesperetin and gardenin A dramatically suppressed ROS and IL-5 production through distinct pathways. Interestingly, hesperidin induced HO-1 expression through the transcription factor Nrf2 coupled with the PI3K/AKT or ERK/JNK signaling pathway, consequently downregulating NFAT activity and IL-5 secretion. Likewise, gardenin A induced HO-1 expression and subsequently suppressed IL-5 production by reducing NFAT activity and upregulating PPARγ in EL-4 cells, suggesting that inducing HO-1 expression may inhibit asthmatic inflammation. Altogether, hesperidin and gardenin A have great potential for regulating the asthma-associated immune responses through antioxidant properties.

中文翻译：

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柑橘类黄酮通过PMA /离子霉素诱导的EL-4细胞中的不同途径抑制IL-5和ROS。

白细胞介素5（IL-5）强烈引发哮喘炎症反应，通过氧化应激的产生，全世界每年影响3亿哮喘患者。柑橘类黄酮具有有益的特性，例如抗炎和抗氧化特性，但抑制哮喘炎症反应的确切分子机制仍不清楚。这项研究的目的是研究在PMA /离子霉素诱导的EL-4细胞中柑桔类黄酮处理可降低ROS和IL-5的潜在机制。我们的结果表明橙皮素和gardenin A通过不同的途径显着抑制了ROS和IL-5的产生。有趣的是，橙皮苷通过转录因子Nrf2结合PI3K / AKT或ERK / JNK信号传导途径诱导HO-1表达，因此下调NFAT活性和IL-5分泌。同样，garden子蛋白A诱导HO-1表达，并随后通过降低NFAT活性和上调EL-4细胞中的PPARγ抑制IL-5的产生，这表明诱导HO-1表达可以抑制哮喘炎症。橙皮苷和garden子苷A总共具有通过抗氧化特性调节与哮喘相关的免疫反应的巨大潜力。