Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Zhu, Chao, Wen, Shuang, Li, Junyong, Meng, Hongyu, Zhang, Junzhe, Zhao, Kuo, Wang, Ling, Zhang, Yingze
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove 2021
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
_version_ 1783693067548622848
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
work_keys_str_mv AT zhuchao fty720inhibitsthedevelopmentofcollageninducedarthritisinmicebysuppressingtherecruitmentofcd4tlymphocytes
AT wenshuang fty720inhibitsthedevelopmentofcollageninducedarthritisinmicebysuppressingtherecruitmentofcd4tlymphocytes
AT lijunyong fty720inhibitsthedevelopmentofcollageninducedarthritisinmicebysuppressingtherecruitmentofcd4tlymphocytes
AT menghongyu fty720inhibitsthedevelopmentofcollageninducedarthritisinmicebysuppressingtherecruitmentofcd4tlymphocytes
AT zhangjunzhe fty720inhibitsthedevelopmentofcollageninducedarthritisinmicebysuppressingtherecruitmentofcd4tlymphocytes
AT zhaokuo fty720inhibitsthedevelopmentofcollageninducedarthritisinmicebysuppressingtherecruitmentofcd4tlymphocytes
AT wangling fty720inhibitsthedevelopmentofcollageninducedarthritisinmicebysuppressingtherecruitmentofcd4tlymphocytes
AT zhangyingze fty720inhibitsthedevelopmentofcollageninducedarthritisinmicebysuppressingtherecruitmentofcd4tlymphocytes