Inhibitory effects of citrus flavonoids on the expression of IL-5 in PMA/Ionomycin-induced EL-4 cells

• Main Authors: Wei-Ling Yang, 楊濰菱
• Other Authors: 顏國欽
• Format: Others
• Language: zh-TW
• Published: 2015
• Online Access: http://ndltd.ncl.edu.tw/handle/77322175265047364779

碩士 === 國立中興大學 === 食品暨應用生物科技學系所 === 103 === Adaptive immune response is usually an ordinary and beneficial regulating function, however, it should be balanced between type 1 helper T-cells (Th1) and Th2 activity. The inability to respond adequately with a Th1 response may result in chronic infection an overactive Th2 immune response may contribute to allergies. Th1/Th2 imbalance towards Th2 response will lead to related Th2 cytokines and antibodies secretion, interleukin 5 (IL-5). IL-5 is a key cytokine produced by Th2 cells, involving in eosinophil growth and differentiation in bone marrow. Dysregulated production of IL-5 by Th2 cells has been linked with eosinophilic inflammatory and allergic diseases. Citrus flavonoids have been reported to possess a variety of beneficial qualities, including anti-viral, anti-inflammatory and anti-oxidant properties. Because of their capacity to inhibit inflammatory reactions, there is potential for citrus flavonoids to improve symptoms of allergies.The aim of this study was to investigate effects of citrus flavonoids on phorbol 12-myristate 13-acetate (PMA) plus ionomycin-induced IL-5 cytokine and reactive oxygen species (ROS) production in Th2 cells, and the underlying mechanism. To evaluate the anti-allergic activity of citrus flavonoids, including nobiletin, tangeretin, 5-demethyl nobiletin (5-DN), hesperetin and gardenin A, the expressions of IL-5 and ROS by PMA/Ionomycin-induced EL-4 cells were determined. Results showed that treatments with six selected citrus flavonoids significantly inhibited the production of IL-5 and ROS, especially hesperidin and gardenin A, by blocking the Th2-related nuclear transcription factors including nuclear factor of activated T cells (NFAT) or activator protein 1 (AP-1). We found that citrus flavonoids inhibited NFAT, which might in turn downregulate Th2-allergic inflammatory responses; therefore, citrus flavonoids might suppress IL-5 and ROS expression by inhibiting NFAT activation. We further investigates the relationship between hesperetin as well as gardenin-A and nuclear transcription factors nuclear factor-erythroid 2 related factor 2 (Nrf2) and peroxisome proliferators activated receptor γ (PPARγ), because of their anti-inflammatory or anti-oxidative roles in the immune system. In this studies, we showed that activation of Nrf2 and HO-1 via increasing the phosphorylation of phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) might play an important role in the hesperidin-induced inhibition of NFAT expression in EL-4 cells.Furthermore, gardenin A can activate PPARγ and HO-1 via downregulation of AP-1, hence decreasing the production of IL-5 and ROS by PMA and Ionomycin. This study suggests that downregulation of NFAT via the activation of Nrf2 and PPARγ might contribute to the inhibitory effect of those citrus flavonoids (hesperidin and gardenin A) on mitogen-induced IL-5 and ROS production in EL-4 cells. Furthermore, citrus flavonoids (hesperidin and gardenin A) is potential to regulate immune homeostasis and anti-allergic properties.