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Article

Co-Stimulation with TWEAK and TGF-β1 Induces Steroid-Insensitive TSLP and CCL5 Production in BEAS-2B Human Bronchial Epithelial Cells

by
Sumiko Abe
1,
Norihiro Harada
1,2,3,*,
Yuuki Sandhu
1,
Hitoshi Sasano
1,
Yuki Tanabe
1,
Shoko Ueda
1,
Takayasu Nishimaki
1,
Yoshihiko Sato
1,
Tomohito Takeshige
1,
Sonoko Harada
1,3,
Hisaya Akiba
4 and
Kazuhisa Takahashi
1,2
1
Department of Respiratory Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo 113-8421, Japan
2
Research Institute for Diseases of Old Ages, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo 113-8421, Japan
3
Atopy (Allergy) Research Center, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo 113-8421, Japan
4
Department of Immunology, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo 113-8421, Japan
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2024, 25(21), 11625; https://doi.org/10.3390/ijms252111625
Submission received: 21 July 2024 / Revised: 22 October 2024 / Accepted: 28 October 2024 / Published: 29 October 2024
(This article belongs to the Special Issue Molecular Research of Epithelial Function and Barrier Dysfunction)
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Abstract

Steroid-resistant asthma is a common cause of refractory asthma. Type 2 inflammation is the main inflammatory response in asthma, and the mechanism underlying the steroid-resistance of type 2 inflammation has not been completely elucidated. Tumor-necrosis-factor-like apoptosis-inducing factor (TWEAK) and transforming growth factor (TGF)-β1 are involved in epithelial–mesenchymal transition (EMT) and the production of thymic stromal lymphopoietin (TSLP) and C-C motif chemokine ligand 5 (CCL5). We herein hypothesize that the combined exposure to TWEAK and TGF-β1 may result in the development of steroid resistance in bronchial epithelial cells. The bronchial epithelial cell line BEAS-2B was cultured with or without TGF-β1 or TWEAK, in the presence or absence of dexamethasone (DEX). The roles of Smad-independent pathways and MAP kinase phosphatase 1 (MKP-1) were also explored. Co-stimulation of TWEAK and TGF-β1 induced E-cadherin reduction, N-cadherin upregulation, and TSLP and CCL5 production, which were not suppressed by DEX. Inhibition of the nuclear factor kappa beta (NF-κB) and mitogen-activated protein kinase pathways downregulated steroid-unresponsive TSLP and CCL5 production, whereas knockdown of MKP-1 improved steroid-unresponsive TSLP production, induced by co-stimulation with TWEAK and TGF-β1. Therefore, co-stimulation with TWEAK and TGF-β1 can induce the steroid-insensitive production of TSLP and CCL5 in the bronchial epithelium and may contribute to airway inflammation.
Keywords: asthma; EMT; TWEAK; TGF-β1; TSLP; CCL5; MKP-1 asthma; EMT; TWEAK; TGF-β1; TSLP; CCL5; MKP-1

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MDPI and ACS Style

Abe, S.; Harada, N.; Sandhu, Y.; Sasano, H.; Tanabe, Y.; Ueda, S.; Nishimaki, T.; Sato, Y.; Takeshige, T.; Harada, S.; et al. Co-Stimulation with TWEAK and TGF-β1 Induces Steroid-Insensitive TSLP and CCL5 Production in BEAS-2B Human Bronchial Epithelial Cells. Int. J. Mol. Sci. 2024, 25, 11625. https://doi.org/10.3390/ijms252111625

AMA Style

Abe S, Harada N, Sandhu Y, Sasano H, Tanabe Y, Ueda S, Nishimaki T, Sato Y, Takeshige T, Harada S, et al. Co-Stimulation with TWEAK and TGF-β1 Induces Steroid-Insensitive TSLP and CCL5 Production in BEAS-2B Human Bronchial Epithelial Cells. International Journal of Molecular Sciences. 2024; 25(21):11625. https://doi.org/10.3390/ijms252111625

Chicago/Turabian Style

Abe, Sumiko, Norihiro Harada, Yuuki Sandhu, Hitoshi Sasano, Yuki Tanabe, Shoko Ueda, Takayasu Nishimaki, Yoshihiko Sato, Tomohito Takeshige, Sonoko Harada, and et al. 2024. "Co-Stimulation with TWEAK and TGF-β1 Induces Steroid-Insensitive TSLP and CCL5 Production in BEAS-2B Human Bronchial Epithelial Cells" International Journal of Molecular Sciences 25, no. 21: 11625. https://doi.org/10.3390/ijms252111625

APA Style

Abe, S., Harada, N., Sandhu, Y., Sasano, H., Tanabe, Y., Ueda, S., Nishimaki, T., Sato, Y., Takeshige, T., Harada, S., Akiba, H., & Takahashi, K. (2024). Co-Stimulation with TWEAK and TGF-β1 Induces Steroid-Insensitive TSLP and CCL5 Production in BEAS-2B Human Bronchial Epithelial Cells. International Journal of Molecular Sciences, 25(21), 11625. https://doi.org/10.3390/ijms252111625

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