[논문]Compound K ameliorates airway inflammation and mucus secretion through the regulation of PKC signaling in vitro and in vivo

Lee, Jae-Won; Kim, Mun-Ock; Song, Yu Na; Min, Jae-Hong; Kim, Seong-Man; Kang, Myung-Ji; Oh, Eun Sol; Lee, Ro Woon; Jung, Sunin; Ro, Hyunju; Lee, Jae Kyoung; Ryu, Hyung Won; Lee, Dae Young; Lee, Su Ui

doi:10.1016/j.jgr.2021.12.008

Compound K ameliorates airway inflammation and mucus secretion through the regulation of PKC signaling in vitro and in vivo 원문보기

Journal of ginseng research = 高麗人參學會誌, v.46 no.3, 2022년, pp.496 - 504

Lee, Jae-Won (Natural Medicine Research Center, KRIBB) , Kim, Mun-Ock (Natural Medicine Research Center, KRIBB) , Song, Yu Na (Natural Medicine Research Center, KRIBB) , Min, Jae-Hong (Natural Medicine Research Center, KRIBB) , Kim, Seong-Man (Natural Medicine Research Center, KRIBB) , Kang, Myung-Ji (Natural Medicine Research Center, KRIBB) , Oh, Eun Sol (Natural Medicine Research Center, KRIBB) , Lee, Ro Woon (Natural Medicine Research Center, KRIBB) , Jung, Sunin (Natural Medicine Research Center, KRIBB) , Ro, Hyunju (Department of Biological Sciences, College of Bioscience and Biotechnology, Chungnam National University) , Lee, Jae Kyoung (Rpbio Research Institute, Rpbio Co. Ltd) , Ryu, Hyung Won (Natural Medicine Research Center, KRIBB) , Lee, Dae Young (Department of Herbal Crop Research, National Institute of Horticultural and Herbal Science, RDA) , Lee, Su Ui (Natural Medicine Research Center, KRIBB)

Abstract ▼ AI-Helper

Background: Cigarette smoke (CS) is considered a principal cause of chronic obstructive pulmonary disease (COPD) and is associated with mucus hypersecretion and airway inflammation. Ginsenoside compound K (CK), a product of ginsenoside metabolism, has various biological activities. Studies on the effects of CK for the treatment of COPD and mucus hypersecretion, including the underlying signaling mechanism, have not yet been conducted. Methods: To study the protective effects and molecular mechanism of CK, phorbol 12-myristate 13-acetate (PMA)-induced human airway epithelial (NCI-H292) cells were used as a cellular model of airway inflammation. An experimental mouse COPD model was also established via CS inhalation and intranasal administration of lipopolysaccharide. Mucin 5AC (MUC5AC), monocyte chemoattractant protein-1, tumor necrosis factor-α (TNF-α), and interleukin-6 secretion, as well as elastase activity and reactive oxygen species production, were determined through enzyme-linked immunosorbent assay. Inflammatory cell influx and mucus secretion in mouse lung tissues were estimated using hematoxylin and eosin and periodic acid-schiff staining, respectively. PKCδ and its downstream signaling molecules were analyzed via western blotting. Results: CK prevented the secretion of MUC5AC and TNF-α in PMA-stimulated NCI-H292 cells and exhibited a protective effect in COPD mice via the suppression of inflammatory mediators and mucus secretion. These effects were accompanied by an inactivation of PKCδ and related signaling in vitro and in vivo. Conclusion: CK suppressed pulmonary inflammation and mucus secretion in COPD mouse model through PKC regulation, highlighting the compound's potential as a useful adjuvant in the prevention and treatment of COPD.

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표/그림 (6)

그림 Fig. 1. Effects of CK on TNF-α and MUC5AC expression in PMA-stimulated NCI-H292 cells. (A) The viability of NCI-H292 cells was evaluated after treatment with CK (1, 2, and 4 μM) in the presence (white bars) or absence (black bars) of PMA using CCK-8 assay. (B-C) The effects of CK on TNF-α and MUC5AC secretion were analyzed by ELISA. NCI-H292 cells were pretreated with the respective concentration of CK for 2 h, followed by treatment with PMA (100 nM). TNF-α was measured at 8 h, and MUC5AC was assessed at various time points. The control in MUC5AC secretion is group without PMA in response time for 3 h (white triangle). (D) The suppressive effects of CK on MUC5AC transcription are shown. HEK293T cells were transiently transfected with a luciferase reporter gene fused to the MUC5AC promoter (HEK293T/MUC5AC promoter-Luc) for 16-18 h, pretreated with corresponding concentration of CK for 2 h, and were then treated with PMA (100 nM) for 12 h. (E) The viability of HEK293T cells was measured by CCK-8 assay after treatment with CK in the presence (white bars) or absence (black bars) of PMA. Data are represented as the mean ± standard deviation from three independent experiments. #p < 0.05 vs. negative control group (without PMA); *p < 0.05, **p < 0.01, and ***p < 0.001 vs. PMA only group.
그림 Fig. 2. Effects of CK on PMA-induced PKCd and its downstream molecules in NCI-H292 cells. NCI-H292 cells were added with the respective concentration of CK for 2 h and subsequently treated with PMA (1 μM) for 15 or 30 min. Total cell lysates were analyzed via western blotting using (A) phospho(p)-NF-κB, NF-κB, p-mTOR, and mTOR; (B) p-JNK, JNK, p-ERK, and ERK; (C) EGR-1, p-RSK, RSK, p-CREB and CREB; (D) p-PKCδ and PKCδ antibodies. Anti-β-actinwas chosen as an internal loading control. The numbers underneath the bands indicate the relative band intensity (fold change relative to the control). (E) The effect of CK combined with rottlerin (selective PKCδ inhibitor). TNF-α and MUC5AC secretion levels were measured using an ELISA assay. Individual bars indicate means ± S.D. for three separate experiments. #p < 0.05 vs. negative control group (without PMA); ***p < 0.001 vs. PMA only group.
그림 Fig. 3. Effects of CK on airway inflammation in COPD mouse models. The results of (A) ROS production, (B) elastase activity, (C) IL-6, and (D) TNF-α production in the BALF of COPD mice. NC: normal control mice; COPD: CS- and LPS (CS/LPS)-exposed COPD mice; ROF: CS/LPS-exposed mice treated with roflumilast (ROF, 5 mg/kg); CK2.5: CS/LPS-exposed mice treated with compound K (CK, 2.5 mg/kg). Data are expressed as the mean ± standard deviation (n = 6). #p < 0.05 vs. negative control group; *p < 0.05 vs. COPD only group.
그림 Fig. 4. Effects of CK on inflammatory cell influx and mucus secretion in the COPD mouse model. The numbers of (A) neutrophils and (B) macrophages in BALF from COPD mice were determined via Diff-Quik staining. (C) ELISAwas employed for the detection of MCP-1 levels in BALF from COPD mice. (D) H&E stainwas used to assess the presence of inflammatory cells around peribronchial lesions ( × 100 magnification; scale bar, 100 μm). Blue arrows indicate inflammatory cells. (E) Periodic acid-Schiff staining was done to assess the production of mucus in airway epithelium ( × 400 magnification; scale bar, 25 μm). The triangular arrows indicate mucus production. NC: normal control mice; COPD: CS and LPS (CS/LPS)-exposed COPD mice; ROF: CS/LPS expose-induced mice treated with roflumilast (ROF, 5 mg/kg); CK2.5: CS/LPS expose-induced mice treated with compound K (CK, 2.5 mg/kg). Data are expressed as the mean ± standard deviation (n = 6). #p < 0.05 vs. negative control group; *p < 0.05 and **p < 0.01 vs. COPD only group.
그림 Fig. 5. Effect of CK on PKCd and its downstream molecules in the lung tissue of COPD mouse. (A) The activation levels of p-NF-κB, NF-κB, p-p70S6K, p70S6K, p-mTOR, and mTOR; (B) p-JNK, JNK, p-ERK, and ERK; (C) EGR-1, p-RSK, RSK, p-CREB, and CREB; (D) p-PKCδ and PKCδ in lung tissue lysates from COPD mice were detected viaWestern blot analysis. Anti-β-actin was chosen as an internal loading control. NC: normal control mice; COPD: CS and LPS (CS/LPS)-exposed COPD mice; ROF: CS/LPS-exposed mice treated with roflumilast (ROF, 5 mg/kg); CK2.5: CS/LPS-exposed mice treated with compound K (CK, 2.5 mg/kg). The numbers underneath the bands indicate the relative band intensity (fold change relative to control).
그림 Fig. 6. Proposed molecular mechanism for the CK-induced inhibition of inflammatory mediators and mucus production in human lung airway epithelial cells and COPD mouse models. PMA and CS promote EGFR-mediated PKCδ phosphorylation and vice versa. In this experiment, the increased phosphorylation of PKCδ, JNK, and ERK as confirmed in both CS/LPS-exposed mice and PMA-treated cells. CK inhibited the expression level of inflammatory factors such as IL-6 and TNF-α as well as that of MUC5AC, both in vitro and in vivo. Our results suggest that the inhibitory effect of CK on cytokine expression may be mediated via inhibition of PKCδ, and its downstream effectors such as MAPKs and mTOR. PKCδ (number 1) and MAPKs (ERK and JNK, number 2) are presumably affected by CK, leading to the inhibition of inflammation-related transcription factors including NF-κB, EGR-1, and CREB. Taken together, CK inhibits JNK/mTOR/NF-κB, MEK/ERK/EGR-1, and ERK/RSK/CREB axis through the suppression of PKCδ activity. TM: transmembrane.

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