[논문]Kaempferol Regulates the Expression of Airway MUC5AC Mucin Gene via IκBα-NF-κB p65 and p38-p44/42-Sp1 Signaling Pathways

Li, Xin; Jin, Fengri; Lee, Hyun Jae; Lee, Choong Jae

doi:10.4062/biomolther.2020.149

[국내논문] Kaempferol Regulates the Expression of Airway MUC5AC Mucin Gene via IκBα-NF-κB p65 and p38-p44/42-Sp1 Signaling Pathways 원문보기

Biomolecules & therapeutics, v.29 no.3, 2021년, pp.303 - 310

Li, Xin (Department of Pharmacology, School of Medicine, Chungnam National University) , Jin, Fengri (Department of Pharmacology, School of Medicine, Chungnam National University) , Lee, Hyun Jae (Smith Liberal Arts College and Department of Addiction Science, Graduate School, Sahmyook University) , Lee, Choong Jae (Department of Pharmacology, School of Medicine, Chungnam National University)

Abstract ▼ AI-Helper

In the present study, kaempferol, a flavonoidal natural compound found in Polygonati Rhizoma, was investigated for its potential effect on the gene expression and production of airway MUC5AC mucin. A human respiratory epithelial NCI-H292 cells was pretreated with kaempferol for 30 min and stimulated with epidermal growth factor (EGF) or phorbol 12-myristate 13-acetate (PMA), for the following 24 h. The effect on PMA-induced nuclear factor kappa B (NF-κB) signaling pathway or EGF-induced mitogen-activated protein kinase (MAPK) signaling pathway was investigated. Kaempferol suppressed the production and gene expression of MUC5AC mucins, induced by PMA through the inhibition of degradation of inhibitory kappa Bα (IκBα), and NF-κB p65 nuclear translocation. Also, kaempferol inhibited EGF-induced gene expression and production of MUC5AC mucin through regulating the phosphorylation of EGFR, phosphorylation of p38 MAPK and extracellular signal-regulated kinase (ERK) 1/2 (p44/42), and the nuclear expression of specificity protein-1 (Sp1). These results suggest kaempferol regulates the gene expression and production of mucin through regulation of NF-κB and MAPK signaling pathways, in human airway epithelial cells.

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표/그림 (7)

그림 Fig. 1. Chemical structure of kaempferol.
그림 Fig. 2. Effect of kaempferol on PMA- or EGF-induced MUC5AC mucin gene expression from NCI-H292 cells. NCI-H292 cells were pretreated with varying concentrations of kaempferol for 30 min and then stimulated with PMA (10 ng/mL) or EGF (25 ng/mL), for 24 h. Cell lysates were collected for measurement of MUC5AC gene expression using RT-PCR. Three independent experiments were performed, and the representative data were shown. *Significantly different from control (p<0.05). ^†Significantly different from PMA (A) or EGF (B) alone (p<0.05). cont: control, K: kaempferol, concentration unit is μM.
그림 Fig. 3. Effect of kaempferol on PMA- or EGF-induced MUC5AC mucin production from NCI-H292 cells. NCI-H292 cells were pretreated with varying concentrations of kaempferol for 30 min and then stimulated with PMA (10 ng/mL) or EGF (25 ng/mL), for 24 h. Cell lysates were collected for measurement of MUC5AC mucin production by ELISA. Each bar represents a mean ± SEM of 3 culture wells compared to the control set at 100%. Three independent experiments were performed, and the representative data were shown. *Significantly different from control (p<0.05). ^†Significantly different from PMA (A) or EGF (B) alone (p<0.05). cont: control, K: kaempferol, concentration unit is μM.
$Fig. 4. Effect of kaempferol on PMA-induced phosphorylation and degradation of IκBα in NCI-H292 cells. NCI-H292 cells were incubated with varying concentrations of kaempferol for 24 h and treated with 50 ng/mL PMA for 30 min. Cytoplasmic extracts were fractionated and then subjected to western blot analysis using phospho-specific IκBα (Ser 32/36) antibody or anti-IκBα antibody. Equal protein loading was evaluated by β-actin levels. The results shown are the representative of three independent experiments. *Significantly different from control (p<0.05). <sup>†</sup>Significantly different from PMA alone (p<0.05). cont: control, K: kaempferol, P: PMA, IκBα: inhibitory kappa B alpha, concentration unit is μM.$ 그림 Fig. 4. Effect of kaempferol on PMA-induced phosphorylation and degradation of IκBα in NCI-H292 cells. NCI-H292 cells were incubated with varying concentrations of kaempferol for 24 h and treated with 50 ng/mL PMA for 30 min. Cytoplasmic extracts were fractionated and then subjected to western blot analysis using phospho-specific IκBα (Ser 32/36) antibody or anti-IκBα antibody. Equal protein loading was evaluated by β-actin levels. The results shown are the representative of three independent experiments. *Significantly different from control (p<0.05). ^†Significantly different from PMA alone (p<0.05). cont: control, K: kaempferol, P: PMA, IκBα: inhibitory kappa B alpha, concentration unit is μM.
그림 Fig. 5. Effect of kaempferol on PMA-induced phosphorylation and translocation of NF-κB p65 in NCI-H292 cells. Nuclear protein extracts were prepared and subjected to western blot analysis using phospho-specific p65 (Ser 536) antibody and antibody against p65. As a loading control, p84 levels were analyzed. The results shown are the representative of three independent experiments. *Significantly different from control (p<0.05). ^†Significantly different from PMA alone (p<0.05). cont: control, K: kaempferol, P: PMA, concentration unit is μM.
그림 Fig. 6. Effect of kaempferol on the expression and phosphorylation of EGFR and the phosphorylation of MEK1/2 in NCI-H292 cells. NCI-H292 cells were pretreated with varying concentrations of kaempferol for 15 min and then stimulated with epidermal growth factor (EGF) (25 ng/mL) for 24 h. Whole cell extract was collected and western blot analysis of the cellular proteins with anti-EGFR, anti-phospho-EGFR (Y1068), and anti-phospho-MEK1/2 (Ser221) antibodies was conducted. Three independent experiments were performed and the representative data were shown. *Significantly different from control (p<0.05). ^†Significantly different from EGF alone (p<0.05). cont: control, K: kaempferol, E: EGF, EGFR: EGF receptor, MEK: MAP kinase kinase, concentration unit is μM.
그림 Fig. 7. Effect of kaempferol on the phosphorylation of p38 and p44/42 and the nuclear expression of Sp1 in NCI-H292 cells. NCIH292 cells were pretreated with varying concentrations of kaempferol for 24 h and then stimulated with epidermal growth factor (EGF) (25 ng/mL) for 60 min. Whole cell extract was collected and western blot analysis of the cellular proteins with anti-phospho-p38 MAPK (Thr180/Tyr182) and anti-phospho-p44/42 (Thr202/Tyr204) antibodies was conducted. Nuclear protein extracts were prepared and subjected to western blot analysis using antibody against Sp1. As a loading control, p84 levels were analyzed. Three independent experiments were performed and the representative data were shown. cont: control, K: kaempferol, E: EGF, MAPK: mitogen-activated protein kinase, ERK: extracellular signal-regulated kinase, Sp1: specificity protein-1, concentration unit is μM. *Significantly different from control (p<0.05). ^†Significantly different from PMA alone (p<0.05). cont: control, K: kaempferol, concentration unit is μM.

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