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FTY720 Inhibits the Development of Collagen-Induced Arthritis in Mice by Suppressing the Recruitment of CD4(+) T Lymphocytes
BACKGROUND: Fingolimod (FTY720), a novel immunomodulator, was found to suppress the severity of collagen-induced arthritis (CIA) in mice. However, the potential molecular mechanisms are still unknown, and the effect of FTY720 on the recruitment of immune cells in the affected joints in the CIA model...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Dove
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8123953/ https://www.ncbi.nlm.nih.gov/pubmed/34007158 http://dx.doi.org/10.2147/DDDT.S293876 |
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author | Zhu, Chao Wen, Shuang Li, Junyong Meng, Hongyu Zhang, Junzhe Zhao, Kuo Wang, Ling Zhang, Yingze |
author_facet | Zhu, Chao Wen, Shuang Li, Junyong Meng, Hongyu Zhang, Junzhe Zhao, Kuo Wang, Ling Zhang, Yingze |
author_sort | Zhu, Chao |
collection | PubMed |
description | BACKGROUND: Fingolimod (FTY720), a novel immunomodulator, was found to suppress the severity of collagen-induced arthritis (CIA) in mice. However, the potential molecular mechanisms are still unknown, and the effect of FTY720 on the recruitment of immune cells in the affected joints in the CIA model is not clear. MATERIALS AND METHODS: Following the oral administration of FTY720 (2 mg/kg) was treated into CIA mice per day for 35 days, intravital microscopy and immunofluorescence assays were performed to examine immune cell recruitment in the affected joints. Human MH7A synoviocytes were stimulated with tumour necrosis factor (TNF)-α and incubated with FTY720. Interleukin-1β (IL-1β), interleukin-6 (IL-6), and interleukin-8 (IL-8) mRNA and protein expression were evaluated using RT-PCR and enzyme-linked immunosorbent assay, respectively. Signal transduction pathway protein expression was measured by Western blotting. Nuclear translocation of nuclear factor (NF)-κB was also analyzed by fluorescence microscopy. RESULTS: In vivo experiments showed that FTY720 inhibited the recruitment of CD4(+) lymphocytes in the affected joints of CIA mice. FTY720 reduced the secretion of IL-1β, IL-6, and IL-8 from TNF-α-stimulated MH7A cells in a dose-dependent manner. FTY720 also inhibited TNF-α-induced phosphorylation of NF-κBp65 and IκBα, as well as NF-κBp65 nuclear translocation, in a dose- and time-dependent manner. Interestingly, FTY720 blocked PI3K/Akt, the upstream targets of the NF-κB pathway. CONCLUSION: Our findings demonstrated that oral administration of FTY720 exerted beneficial effects in CIA mice by inhibiting CD4(+) T lymphocyte recruitment to the affected joints. Our data also indicated that FTY720 inhibited TNF-α-induced inflammation by suppressing the AKT/PI3K/NF-κB pathway in MH7A cells. |
format | Online Article Text |
id | pubmed-8123953 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Dove |
record_format | MEDLINE/PubMed |
spelling | pubmed-81239532021-05-17 FTY720 Inhibits the Development of Collagen-Induced Arthritis in Mice by Suppressing the Recruitment of CD4(+) T Lymphocytes Zhu, Chao Wen, Shuang Li, Junyong Meng, Hongyu Zhang, Junzhe Zhao, Kuo Wang, Ling Zhang, Yingze Drug Des Devel Ther Original Research BACKGROUND: Fingolimod (FTY720), a novel immunomodulator, was found to suppress the severity of collagen-induced arthritis (CIA) in mice. However, the potential molecular mechanisms are still unknown, and the effect of FTY720 on the recruitment of immune cells in the affected joints in the CIA model is not clear. MATERIALS AND METHODS: Following the oral administration of FTY720 (2 mg/kg) was treated into CIA mice per day for 35 days, intravital microscopy and immunofluorescence assays were performed to examine immune cell recruitment in the affected joints. Human MH7A synoviocytes were stimulated with tumour necrosis factor (TNF)-α and incubated with FTY720. Interleukin-1β (IL-1β), interleukin-6 (IL-6), and interleukin-8 (IL-8) mRNA and protein expression were evaluated using RT-PCR and enzyme-linked immunosorbent assay, respectively. Signal transduction pathway protein expression was measured by Western blotting. Nuclear translocation of nuclear factor (NF)-κB was also analyzed by fluorescence microscopy. RESULTS: In vivo experiments showed that FTY720 inhibited the recruitment of CD4(+) lymphocytes in the affected joints of CIA mice. FTY720 reduced the secretion of IL-1β, IL-6, and IL-8 from TNF-α-stimulated MH7A cells in a dose-dependent manner. FTY720 also inhibited TNF-α-induced phosphorylation of NF-κBp65 and IκBα, as well as NF-κBp65 nuclear translocation, in a dose- and time-dependent manner. Interestingly, FTY720 blocked PI3K/Akt, the upstream targets of the NF-κB pathway. CONCLUSION: Our findings demonstrated that oral administration of FTY720 exerted beneficial effects in CIA mice by inhibiting CD4(+) T lymphocyte recruitment to the affected joints. Our data also indicated that FTY720 inhibited TNF-α-induced inflammation by suppressing the AKT/PI3K/NF-κB pathway in MH7A cells. Dove 2021-05-11 /pmc/articles/PMC8123953/ /pubmed/34007158 http://dx.doi.org/10.2147/DDDT.S293876 Text en © 2021 Zhu et al. https://creativecommons.org/licenses/by-nc/3.0/This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/ (https://creativecommons.org/licenses/by-nc/3.0/) ). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). |
spellingShingle | Original Research Zhu, Chao Wen, Shuang Li, Junyong Meng, Hongyu Zhang, Junzhe Zhao, Kuo Wang, Ling Zhang, Yingze FTY720 Inhibits the Development of Collagen-Induced Arthritis in Mice by Suppressing the Recruitment of CD4(+) T Lymphocytes |
title | FTY720 Inhibits the Development of Collagen-Induced Arthritis in Mice by Suppressing the Recruitment of CD4(+) T Lymphocytes |
title_full | FTY720 Inhibits the Development of Collagen-Induced Arthritis in Mice by Suppressing the Recruitment of CD4(+) T Lymphocytes |
title_fullStr | FTY720 Inhibits the Development of Collagen-Induced Arthritis in Mice by Suppressing the Recruitment of CD4(+) T Lymphocytes |
title_full_unstemmed | FTY720 Inhibits the Development of Collagen-Induced Arthritis in Mice by Suppressing the Recruitment of CD4(+) T Lymphocytes |
title_short | FTY720 Inhibits the Development of Collagen-Induced Arthritis in Mice by Suppressing the Recruitment of CD4(+) T Lymphocytes |
title_sort | fty720 inhibits the development of collagen-induced arthritis in mice by suppressing the recruitment of cd4(+) t lymphocytes |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8123953/ https://www.ncbi.nlm.nih.gov/pubmed/34007158 http://dx.doi.org/10.2147/DDDT.S293876 |
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