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Plumbagin Ameliorates Collagen-Induced Arthritis by Regulating Treg/Th17 Cell Imbalances and Suppressing Osteoclastogenesis

Objective: Plumbago zeylanica L. (with plumbagin as its active ingredients) has been used for centuries to treat conditions such as joint swelling, fractures, and bacterial infections, suggesting that it possesses anti-inflammatory and immunosuppressive properties. In the present study, we evaluated...

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Autores principales: Wang, Tingyu, Qiao, Han, Zhai, Zanjing, Zhang, Jun, Tu, Jinwen, Zheng, Xinyi, Qian, Niandong, Zhou, Hong, Lu, Eryi, Tang, Tingting
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333053/
https://www.ncbi.nlm.nih.gov/pubmed/30671063
http://dx.doi.org/10.3389/fimmu.2018.03102
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author Wang, Tingyu
Qiao, Han
Zhai, Zanjing
Zhang, Jun
Tu, Jinwen
Zheng, Xinyi
Qian, Niandong
Zhou, Hong
Lu, Eryi
Tang, Tingting
author_facet Wang, Tingyu
Qiao, Han
Zhai, Zanjing
Zhang, Jun
Tu, Jinwen
Zheng, Xinyi
Qian, Niandong
Zhou, Hong
Lu, Eryi
Tang, Tingting
author_sort Wang, Tingyu
collection PubMed
description Objective: Plumbago zeylanica L. (with plumbagin as its active ingredients) has been used for centuries to treat conditions such as joint swelling, fractures, and bacterial infections, suggesting that it possesses anti-inflammatory and immunosuppressive properties. In the present study, we evaluated the potential anti-arthritic activity and related mechanisms of plumbagin. Methods: Collagen-induced arthritis (CIA) was initiated in Wistar rats with collagen type II. Plumbagin (2 and 6 mg/kg) was orally administered to rats with CIA from day 12 to day 32 post immunization. The effects of plumbagin on arthritis progression were assessed by paw swelling, clinical scoring, and histologic analysis. The percentage of Treg and Th17 were defined by flow cytometry or immunofluorescence (IF) staining. Bone erosion and resorption were assessed by micro-CT and histomorphometric analysis. Osteoclast differentiation was further determined by in vitro osteoclastogenesis assay. The molecular docking assay was used to determine the potential binding site of plumbagin. Results: Treatment with plumbagin significantly inhibited arthritis development, as well as suppressed the local and systemic inflammation. Plumbagin reciprocally regulated pro-inflammatory Th17 cell and immunosuppressive Treg cell populations. In addition, plumbagin protected inflammation-induced bone loss by inhibiting osteoclast formation and activity. Plumbagin markedly suppressed RANKL-stimulated osteoclast-specific gene expression by repressing NF-κB signaling activation and MAP kinase phosphorylation. Further study via molecular docking assay demonstrated that plumbagin bound to MET169 of JNK kinase and LYS138 and SER183 of p38 kinase. Conclusion: Plumbagin not only attenuates the immune-induced arthritis by inhibiting inflammation, but also protects bone erosion by directly inhibiting osteoclast formation and activity. These data suggest plumbagin is a promising new candidate drug for treating inflammatory joint diseases.
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spelling pubmed-63330532019-01-22 Plumbagin Ameliorates Collagen-Induced Arthritis by Regulating Treg/Th17 Cell Imbalances and Suppressing Osteoclastogenesis Wang, Tingyu Qiao, Han Zhai, Zanjing Zhang, Jun Tu, Jinwen Zheng, Xinyi Qian, Niandong Zhou, Hong Lu, Eryi Tang, Tingting Front Immunol Immunology Objective: Plumbago zeylanica L. (with plumbagin as its active ingredients) has been used for centuries to treat conditions such as joint swelling, fractures, and bacterial infections, suggesting that it possesses anti-inflammatory and immunosuppressive properties. In the present study, we evaluated the potential anti-arthritic activity and related mechanisms of plumbagin. Methods: Collagen-induced arthritis (CIA) was initiated in Wistar rats with collagen type II. Plumbagin (2 and 6 mg/kg) was orally administered to rats with CIA from day 12 to day 32 post immunization. The effects of plumbagin on arthritis progression were assessed by paw swelling, clinical scoring, and histologic analysis. The percentage of Treg and Th17 were defined by flow cytometry or immunofluorescence (IF) staining. Bone erosion and resorption were assessed by micro-CT and histomorphometric analysis. Osteoclast differentiation was further determined by in vitro osteoclastogenesis assay. The molecular docking assay was used to determine the potential binding site of plumbagin. Results: Treatment with plumbagin significantly inhibited arthritis development, as well as suppressed the local and systemic inflammation. Plumbagin reciprocally regulated pro-inflammatory Th17 cell and immunosuppressive Treg cell populations. In addition, plumbagin protected inflammation-induced bone loss by inhibiting osteoclast formation and activity. Plumbagin markedly suppressed RANKL-stimulated osteoclast-specific gene expression by repressing NF-κB signaling activation and MAP kinase phosphorylation. Further study via molecular docking assay demonstrated that plumbagin bound to MET169 of JNK kinase and LYS138 and SER183 of p38 kinase. Conclusion: Plumbagin not only attenuates the immune-induced arthritis by inhibiting inflammation, but also protects bone erosion by directly inhibiting osteoclast formation and activity. These data suggest plumbagin is a promising new candidate drug for treating inflammatory joint diseases. Frontiers Media S.A. 2019-01-08 /pmc/articles/PMC6333053/ /pubmed/30671063 http://dx.doi.org/10.3389/fimmu.2018.03102 Text en Copyright © 2019 Wang, Qiao, Zhai, Zhang, Tu, Zheng, Qian, Zhou, Lu and Tang. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Wang, Tingyu
Qiao, Han
Zhai, Zanjing
Zhang, Jun
Tu, Jinwen
Zheng, Xinyi
Qian, Niandong
Zhou, Hong
Lu, Eryi
Tang, Tingting
Plumbagin Ameliorates Collagen-Induced Arthritis by Regulating Treg/Th17 Cell Imbalances and Suppressing Osteoclastogenesis
title Plumbagin Ameliorates Collagen-Induced Arthritis by Regulating Treg/Th17 Cell Imbalances and Suppressing Osteoclastogenesis
title_full Plumbagin Ameliorates Collagen-Induced Arthritis by Regulating Treg/Th17 Cell Imbalances and Suppressing Osteoclastogenesis
title_fullStr Plumbagin Ameliorates Collagen-Induced Arthritis by Regulating Treg/Th17 Cell Imbalances and Suppressing Osteoclastogenesis
title_full_unstemmed Plumbagin Ameliorates Collagen-Induced Arthritis by Regulating Treg/Th17 Cell Imbalances and Suppressing Osteoclastogenesis
title_short Plumbagin Ameliorates Collagen-Induced Arthritis by Regulating Treg/Th17 Cell Imbalances and Suppressing Osteoclastogenesis
title_sort plumbagin ameliorates collagen-induced arthritis by regulating treg/th17 cell imbalances and suppressing osteoclastogenesis
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333053/
https://www.ncbi.nlm.nih.gov/pubmed/30671063
http://dx.doi.org/10.3389/fimmu.2018.03102
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