Formononetin ameliorates IL‑13‑induced inflammation and mucus formation in human nasal epithelial cells by activating the SIRT1/Nrf2 signaling pathway

Abstract

Formononetin has proven to be anti-inflammatory and able to alleviate symptoms of certain allergic diseases. The present study aimed to determine and elucidate the potential effects of formononetin in allergic rhinitis. JME/CF15 cells were pretreated with formononetin at different doses, followed by stimulation with IL-13. Cell Counting Kit-8 assay was performed to determine the cytotoxicity of formononetin. The expression levels of inflammation-related proteins, histamine, IgE, TNF-α, IL-1β, IL-6, granulocyte-macrophage colony-stimulating factor and eotaxin in IL-13-stimulated JME/CF15 cells were detected using ELISAs. The expression levels of phosphorylated-NF-κB p65, NF-κB p65 and cyclooxygenase-2 (Cox-2) were analyzed using western blotting. Reverse transcription-quantitative PCR, western blotting and immunofluorescence were performed to measure the levels of mucin 5AC oligomeric mucus/gel-forming. Expression levels of sirtuin 1 (SIRT1) and nuclear erythroid factor 2-related factor 2 (Nrf2) proteins were also measured using western blotting. The results of the present study revealed that formononetin exerted no cytotoxic effect on the viability of JME/CF15 cells. Following stimulation of JME/CF15 cells with IL-13, formononetin suppressed the upregulated expression levels of proinflammatory cytokines. IL-13-induced formation of mucus was also attenuated by formononetin treatment. Furthermore, it was found that the SIRT1/Nrf2 signaling pathway was activated in formononetin-treated JME/CF15 cells, whereas treatment with the SIRT1 inhibitor, EX527, reversed the effects of formononetin on IL-13-induced inflammation and mucus formation in JME/CF15 cells. In conclusion, the findings of the current study indicated that formononetin may activate the SIRT1/Nrf2 signaling pathway, thereby inhibiting IL-13-induced inflammation and mucus formation in JME/CF15 cells. These results suggested that formononetin may represent a promising agent for the treatment of allergic rhinitis.

HDAC4 depletion ameliorates IL‐13‐triggered inflammatory response and mucus production in nasal epithelial cells via activation of SIRT1/NF‐κB signaling

“…40 IL-13 has been shown to stimulate the production of mucus and inflammatory-related cytokines including IgE, GM-CSF, eotaxin, IL-1β and IL-6. 24 Consistent with these findings, it was also proved that IL-13 treatment markedly elevated the levels of histamine, IgE, GM-CSF, eotaxin, IL-1β, IL-6 and increased the expression of MUC5AC in hNECs. Moreover, insufficiency of HDAC4 distinctly downregulated the levels of histamine, IgE, GM-CSF, eotaxin, IL-1β, IL-6, and cut down MUC5AC expression in IL-13-primed hNECs.…”

“…Several studies have firmly established that high expression of SIRT1 plays a suppressive role in murine allergic rhinitis 23,44 . Furthermore, Huang et al have substantiated that SIRT1 activation mitigates inflammation and mucus formation in IL‐13‐insulted hNECs 24 . NF‐κB signaling is a core pro‐inflammatory signaling relying on NF‐κB activation 45 .…”

“…MUC5AC is a major component of mucus implicated in a series of malignancies as a potential diagnostic, prognostic and therapeutic target 40 . IL‐13 has been shown to stimulate the production of mucus and inflammatory‐related cytokines including IgE, GM‐CSF, eotaxin, IL‐1β and IL‐6 24 . Consistent with these findings, it was also proved that IL‐13 treatment markedly elevated the levels of histamine, IgE, GM‐CSF, eotaxin, IL‐1β, IL‐6 and increased the expression of MUC5AC in hNECs.…”

“…More importantly, Yuan et al have illuminated that SIRT1 plays a protective role in murine allergic rhinitis through inactivation of HMGB1/TLR4 pathway 23 . Huang et al have revealed that SIRT1/Nrf2 signaling modulates the inflammation and mucus formation in human nasal epithelial cells following IL‐13 treatment 24 . However, it has not been reported whether HDAC4 regulates SIRT1 and its downstream pathways in AR.…”

Network Pharmacology and Molecular Docking Study of Yupingfeng Powder in the Treatment of Allergic Diseases

“…Kaempferol, a biological flavonoid, has been reported to block airway inflammation by interfering with TyK-STAT signaling in the airway epithelial cells of asthmatic mice [39]. Formononetin, a phytoestrogen extracted from Huangqi, has been demonstrated to ameliorate IL-13-induced inflammation and mucus formation in human nasal epithelial cells by activating the SIRT1/Nrf2 signaling pathway [40]. With regard to wogonin, it has been proved to reduce allergic airway inflammation by inducing eosinophil apoptosis and regulating T lymphocyte differentiation [41][42][43].…”