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Thrombin-Induced COX-2 Expression and PGE(2) Synthesis in Human Tracheal Smooth Muscle Cells: Role of PKCδ/Pyk2-Dependent AP-1 Pathway Modulation
In this study, we confirmed that thrombin significantly increases the production of COX-2 and PGE(2) in human tracheal smooth muscle cells (HTSMCs), leading to inflammation in the airways and lungs. These molecules are well-known contributors to various inflammatory diseases. Here, we investigated i...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10606820/ https://www.ncbi.nlm.nih.gov/pubmed/37894811 http://dx.doi.org/10.3390/ijms242015130 |
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author | Yang, Chien-Chung Lee, I-Ta Lin, Yan-Jyun Wu, Wen-Bin Hsiao, Li-Der Yang, Chuen-Mao |
author_facet | Yang, Chien-Chung Lee, I-Ta Lin, Yan-Jyun Wu, Wen-Bin Hsiao, Li-Der Yang, Chuen-Mao |
author_sort | Yang, Chien-Chung |
collection | PubMed |
description | In this study, we confirmed that thrombin significantly increases the production of COX-2 and PGE(2) in human tracheal smooth muscle cells (HTSMCs), leading to inflammation in the airways and lungs. These molecules are well-known contributors to various inflammatory diseases. Here, we investigated in detail the involved signaling pathways using specific inhibitors and small interfering RNAs (siRNAs). Our results demonstrated that inhibitors targeting proteins such as protein kinase C (PKC)δ, proline-rich tyrosine kinase 2 (Pyk2), c-Src, epidermal growth factor receptor (EGFR), phosphatidylinositol 3-kinase (PI3K), or activator protein-1 (AP-1) effectively reduced thrombin-induced COX-2 and PGE(2) production. Additionally, transfection with siRNAs against PKCδ, Pyk2, c-Src, EGFR, protein kinase B (Akt), or c-Jun mitigated these responses. Furthermore, our observations revealed that thrombin stimulated the phosphorylation of key components of the signaling cascade, including PKCδ, Pyk2, c-Src, EGFR, Akt, and c-Jun. Thrombin activated COX-2 promoter activity through AP-1 activation, a process that was disrupted by a point-mutated AP-1 site within the COX-2 promoter. Finally, resveratrol (one of the most researched natural polyphenols) was found to effectively inhibit thrombin-induced COX-2 expression and PGE(2) release in HTSMCs through blocking the activation of Pyk2, c-Src, EGFR, Akt, and c-Jun. In summary, our findings demonstrate that thrombin-induced COX-2 and PGE(2) generation involves a PKCδ/Pyk2/c-Src/EGFR/PI3K/Akt-dependent AP-1 activation pathway. This study also suggests the potential use of resveratrol as an intervention for managing airway inflammation. |
format | Online Article Text |
id | pubmed-10606820 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-106068202023-10-28 Thrombin-Induced COX-2 Expression and PGE(2) Synthesis in Human Tracheal Smooth Muscle Cells: Role of PKCδ/Pyk2-Dependent AP-1 Pathway Modulation Yang, Chien-Chung Lee, I-Ta Lin, Yan-Jyun Wu, Wen-Bin Hsiao, Li-Der Yang, Chuen-Mao Int J Mol Sci Article In this study, we confirmed that thrombin significantly increases the production of COX-2 and PGE(2) in human tracheal smooth muscle cells (HTSMCs), leading to inflammation in the airways and lungs. These molecules are well-known contributors to various inflammatory diseases. Here, we investigated in detail the involved signaling pathways using specific inhibitors and small interfering RNAs (siRNAs). Our results demonstrated that inhibitors targeting proteins such as protein kinase C (PKC)δ, proline-rich tyrosine kinase 2 (Pyk2), c-Src, epidermal growth factor receptor (EGFR), phosphatidylinositol 3-kinase (PI3K), or activator protein-1 (AP-1) effectively reduced thrombin-induced COX-2 and PGE(2) production. Additionally, transfection with siRNAs against PKCδ, Pyk2, c-Src, EGFR, protein kinase B (Akt), or c-Jun mitigated these responses. Furthermore, our observations revealed that thrombin stimulated the phosphorylation of key components of the signaling cascade, including PKCδ, Pyk2, c-Src, EGFR, Akt, and c-Jun. Thrombin activated COX-2 promoter activity through AP-1 activation, a process that was disrupted by a point-mutated AP-1 site within the COX-2 promoter. Finally, resveratrol (one of the most researched natural polyphenols) was found to effectively inhibit thrombin-induced COX-2 expression and PGE(2) release in HTSMCs through blocking the activation of Pyk2, c-Src, EGFR, Akt, and c-Jun. In summary, our findings demonstrate that thrombin-induced COX-2 and PGE(2) generation involves a PKCδ/Pyk2/c-Src/EGFR/PI3K/Akt-dependent AP-1 activation pathway. This study also suggests the potential use of resveratrol as an intervention for managing airway inflammation. MDPI 2023-10-13 /pmc/articles/PMC10606820/ /pubmed/37894811 http://dx.doi.org/10.3390/ijms242015130 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Yang, Chien-Chung Lee, I-Ta Lin, Yan-Jyun Wu, Wen-Bin Hsiao, Li-Der Yang, Chuen-Mao Thrombin-Induced COX-2 Expression and PGE(2) Synthesis in Human Tracheal Smooth Muscle Cells: Role of PKCδ/Pyk2-Dependent AP-1 Pathway Modulation |
title | Thrombin-Induced COX-2 Expression and PGE(2) Synthesis in Human Tracheal Smooth Muscle Cells: Role of PKCδ/Pyk2-Dependent AP-1 Pathway Modulation |
title_full | Thrombin-Induced COX-2 Expression and PGE(2) Synthesis in Human Tracheal Smooth Muscle Cells: Role of PKCδ/Pyk2-Dependent AP-1 Pathway Modulation |
title_fullStr | Thrombin-Induced COX-2 Expression and PGE(2) Synthesis in Human Tracheal Smooth Muscle Cells: Role of PKCδ/Pyk2-Dependent AP-1 Pathway Modulation |
title_full_unstemmed | Thrombin-Induced COX-2 Expression and PGE(2) Synthesis in Human Tracheal Smooth Muscle Cells: Role of PKCδ/Pyk2-Dependent AP-1 Pathway Modulation |
title_short | Thrombin-Induced COX-2 Expression and PGE(2) Synthesis in Human Tracheal Smooth Muscle Cells: Role of PKCδ/Pyk2-Dependent AP-1 Pathway Modulation |
title_sort | thrombin-induced cox-2 expression and pge(2) synthesis in human tracheal smooth muscle cells: role of pkcδ/pyk2-dependent ap-1 pathway modulation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10606820/ https://www.ncbi.nlm.nih.gov/pubmed/37894811 http://dx.doi.org/10.3390/ijms242015130 |
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