論文 - 詳細
| RRC ID | 63715 |
|---|---|
| 著者 | Yap JMG, Ueda T, Kanemitsu Y, Takeda N, Fukumitsu K, Fukuda S, Uemura T, Tajiri T, Ohkubo H, Maeno K, Ito Y, Oguri T, Ugawa S, Niimi A. |
| タイトル | AITC inhibits fibroblast-myofibroblast transition via TRPA1-independent MAPK and NRF2/HO-1 pathways and reverses corticosteroids insensitivity in human lung fibroblasts. |
| ジャーナル | Respir Res |
| Abstract |
BACKGROUND:Little is known on the role of transient receptor potential ankyrin 1 (TRPA1) in fibroblast-myofibroblast transition (FMT) that can lead to airway remodeling which is a major problem for severe asthma and fibrosis. Thus, this study investigated the effect of TRPA1 modulators on transforming growth factor beta 1(TGF-β1) -treated lung fibroblasts. METHODS:MRC-5 cells were preincubated with TGF-β1 for 24 h. TRPA1 agonist or antagonist were added and further incubated for 24 h. The changes in TRPA1 and alpha-smooth muscle actin (α-SMA) expressions by stimuli were evaluated using qRT-PCR, western blot and immunohistochemical analyses. Statistical significance was determined by using one- or two-way ANOVA, followed by Bonferroni's post hoc analysis for comparison of multiple groups and paired 2-tailed Student's t-test between 2 groups. RESULTS:MRC-5 cells treated by TGF-β1 significantly upregulated α-SMA mRNA expressions (P < 0.01), but downregulated TRPA1 gene expression (P < 0.001). Post-treatment of TRPA1 activator, allyl isothiocyanate (AITC), after TGF-β1 significantly downregulated the α-SMA gene induction (P < 0.01 at 24 h), protein expression (P < 0.05) and immunoreactivity with stress fibers (P < 0.05). On the other hand, TRPA1 antagonist HC-030031 did not prevent this effect, and instead tended to facilitate the suppressive effect of AITC when co-stimulated. AITC significantly increased phosphorylated- extracellular signal-regulated kinase (ERK) 1/2 and heme oxygenase (HO)-1 protein expressions (P < 0.05) in TGF-β1-treated cells. Combined inhibition with ERK1/2 mitogen-activated protein kinase (MAPK) and nuclear factor erythroid 2-related factor (NRF2) almost completely reversed AITC-induced α-SMA suppression (P < 0.05). Dexamethasone was not able to inhibit the upregulated α-SMA induction by TGF-β1. However, AITC improved dexamethasone-insensitive myodifferentiation in the presence of the corticosteroid (P < 0.01). CONCLUSION:We found that AITC exerts protective effect on TGF-β1-induced α-SMA induction by activating ERK1/2 MAPK and NRF2/HO-1 pathways in lung fibroblasts. It also overcomes corticosteroids insensitivity in TGF-β1-induced α-SMA induction. TRPA1 antagonist modulates the suppressive effect, but not prevent it. AITC and TRPA1 antagonist may be therapeutic agents in treating chronic respiratory diseases. |
| 巻・号 | 22(1) |
| ページ | 51 |
| 公開日 | 2021-2-12 |
| DOI | 10.1186/s12931-021-01636-9 |
| PII | 10.1186/s12931-021-01636-9 |
| PMID | 33579280 |
| PMC | PMC7881560 |
| MeSH | Adrenal Cortex Hormones / toxicity* Fibroblasts / drug effects Fibroblasts / metabolism Heme Oxygenase-1 / metabolism* Humans Isothiocyanates / pharmacology* Lung / drug effects Lung / metabolism* Mitogen-Activated Protein Kinase Kinases / metabolism* Myofibroblasts / drug effects Myofibroblasts / metabolism NF-E2-Related Factor 2 / metabolism* TRPA1 Cation Channel / antagonists & inhibitors TRPA1 Cation Channel / metabolism* Transforming Growth Factor beta1 / toxicity |
| IF | 3.924 |
| リソース情報 | |
| ヒト・動物細胞 | MRC-5(RCB0218) HF19(RCB0210) |