Cargando…
Targeting of Janus Kinases Limits Pro-Inflammatory but Also Immunosuppressive Circuits in the Crosstalk between Synovial Fibroblasts and Lymphocytes
Crosstalk between synovial fibroblasts (SF) and immune cells plays a central role in the development of rheumatoid arthritis (RA). Janus kinase inhibitors (JAKi) have proven efficacy in the treatment of RA, although clinical responses are heterogeneous. Currently, little is known regarding how JAKi...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8533088/ https://www.ncbi.nlm.nih.gov/pubmed/34680530 http://dx.doi.org/10.3390/biomedicines9101413 |
_version_ | 1784587227307704320 |
---|---|
author | Yao, Nina Tretter, Theresa Kvacskay, Peter Merkt, Wolfgang Blank, Norbert Lorenz, Hanns-Martin Tykocinski, Lars-Oliver |
author_facet | Yao, Nina Tretter, Theresa Kvacskay, Peter Merkt, Wolfgang Blank, Norbert Lorenz, Hanns-Martin Tykocinski, Lars-Oliver |
author_sort | Yao, Nina |
collection | PubMed |
description | Crosstalk between synovial fibroblasts (SF) and immune cells plays a central role in the development of rheumatoid arthritis (RA). Janus kinase inhibitors (JAKi) have proven efficacy in the treatment of RA, although clinical responses are heterogeneous. Currently, little is known regarding how JAKi affect pro- and anti-inflammatory circuits in the bidirectional interplay between SF and immune cells. Here, we examined the effects of tofacitinib, baricitinib and upadacitinib on crosstalk between SF and T or B lymphocytes in vitro and compared them with those of biologic disease modifying anti-rheumatic drugs (bDMARDs). JAKi dose-dependently suppressed cytokine secretion of T helper (Th) cells and decreased interleukin (IL)-6 and matrix metalloproteinase (MMP)3 secretion of SF stimulated by Th cells. Importantly, JAK inhibition attenuated the enhanced memory response of chronically stimulated SF. Vice versa, JAKi reduced the indoleamine-2,3-dioxygenase (IDO)1-mediated suppression of T cell-proliferation by SF. Remarkably, certain bDMARDs were as efficient as JAKi in suppressing the IL-6 and MMP3 secretion of SF stimulated by Th (adalimumab, secukinumab) or B cells (canakinumab) and combining bDMARDs with JAKi had synergistic effects. In conclusion, JAKi limit pro-inflammatory circuits in the crosstalk between SF and lymphocytes; however, they also weaken the immunosuppressive functions of SF. Both effects were dose-dependent and may contribute to heterogeneity in clinical response to treatment. |
format | Online Article Text |
id | pubmed-8533088 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-85330882021-10-23 Targeting of Janus Kinases Limits Pro-Inflammatory but Also Immunosuppressive Circuits in the Crosstalk between Synovial Fibroblasts and Lymphocytes Yao, Nina Tretter, Theresa Kvacskay, Peter Merkt, Wolfgang Blank, Norbert Lorenz, Hanns-Martin Tykocinski, Lars-Oliver Biomedicines Article Crosstalk between synovial fibroblasts (SF) and immune cells plays a central role in the development of rheumatoid arthritis (RA). Janus kinase inhibitors (JAKi) have proven efficacy in the treatment of RA, although clinical responses are heterogeneous. Currently, little is known regarding how JAKi affect pro- and anti-inflammatory circuits in the bidirectional interplay between SF and immune cells. Here, we examined the effects of tofacitinib, baricitinib and upadacitinib on crosstalk between SF and T or B lymphocytes in vitro and compared them with those of biologic disease modifying anti-rheumatic drugs (bDMARDs). JAKi dose-dependently suppressed cytokine secretion of T helper (Th) cells and decreased interleukin (IL)-6 and matrix metalloproteinase (MMP)3 secretion of SF stimulated by Th cells. Importantly, JAK inhibition attenuated the enhanced memory response of chronically stimulated SF. Vice versa, JAKi reduced the indoleamine-2,3-dioxygenase (IDO)1-mediated suppression of T cell-proliferation by SF. Remarkably, certain bDMARDs were as efficient as JAKi in suppressing the IL-6 and MMP3 secretion of SF stimulated by Th (adalimumab, secukinumab) or B cells (canakinumab) and combining bDMARDs with JAKi had synergistic effects. In conclusion, JAKi limit pro-inflammatory circuits in the crosstalk between SF and lymphocytes; however, they also weaken the immunosuppressive functions of SF. Both effects were dose-dependent and may contribute to heterogeneity in clinical response to treatment. MDPI 2021-10-08 /pmc/articles/PMC8533088/ /pubmed/34680530 http://dx.doi.org/10.3390/biomedicines9101413 Text en © 2021 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 Yao, Nina Tretter, Theresa Kvacskay, Peter Merkt, Wolfgang Blank, Norbert Lorenz, Hanns-Martin Tykocinski, Lars-Oliver Targeting of Janus Kinases Limits Pro-Inflammatory but Also Immunosuppressive Circuits in the Crosstalk between Synovial Fibroblasts and Lymphocytes |
title | Targeting of Janus Kinases Limits Pro-Inflammatory but Also Immunosuppressive Circuits in the Crosstalk between Synovial Fibroblasts and Lymphocytes |
title_full | Targeting of Janus Kinases Limits Pro-Inflammatory but Also Immunosuppressive Circuits in the Crosstalk between Synovial Fibroblasts and Lymphocytes |
title_fullStr | Targeting of Janus Kinases Limits Pro-Inflammatory but Also Immunosuppressive Circuits in the Crosstalk between Synovial Fibroblasts and Lymphocytes |
title_full_unstemmed | Targeting of Janus Kinases Limits Pro-Inflammatory but Also Immunosuppressive Circuits in the Crosstalk between Synovial Fibroblasts and Lymphocytes |
title_short | Targeting of Janus Kinases Limits Pro-Inflammatory but Also Immunosuppressive Circuits in the Crosstalk between Synovial Fibroblasts and Lymphocytes |
title_sort | targeting of janus kinases limits pro-inflammatory but also immunosuppressive circuits in the crosstalk between synovial fibroblasts and lymphocytes |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8533088/ https://www.ncbi.nlm.nih.gov/pubmed/34680530 http://dx.doi.org/10.3390/biomedicines9101413 |
work_keys_str_mv | AT yaonina targetingofjanuskinaseslimitsproinflammatorybutalsoimmunosuppressivecircuitsinthecrosstalkbetweensynovialfibroblastsandlymphocytes AT trettertheresa targetingofjanuskinaseslimitsproinflammatorybutalsoimmunosuppressivecircuitsinthecrosstalkbetweensynovialfibroblastsandlymphocytes AT kvacskaypeter targetingofjanuskinaseslimitsproinflammatorybutalsoimmunosuppressivecircuitsinthecrosstalkbetweensynovialfibroblastsandlymphocytes AT merktwolfgang targetingofjanuskinaseslimitsproinflammatorybutalsoimmunosuppressivecircuitsinthecrosstalkbetweensynovialfibroblastsandlymphocytes AT blanknorbert targetingofjanuskinaseslimitsproinflammatorybutalsoimmunosuppressivecircuitsinthecrosstalkbetweensynovialfibroblastsandlymphocytes AT lorenzhannsmartin targetingofjanuskinaseslimitsproinflammatorybutalsoimmunosuppressivecircuitsinthecrosstalkbetweensynovialfibroblastsandlymphocytes AT tykocinskilarsoliver targetingofjanuskinaseslimitsproinflammatorybutalsoimmunosuppressivecircuitsinthecrosstalkbetweensynovialfibroblastsandlymphocytes |