Targeting Activated Synovial Fibroblasts in Rheumatoid Arthritis by Peficitinib
Background: Synovial fibroblasts (SF) play a major role in the pathogenesis of rheumatoid arthritis (RA) and develop an aggressive phenotype destroying cartilage and bone, thus termed RASF. JAK inhibitors have shown to be an efficient therapeutic option in RA treatment, but less is known about the e...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-03-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2019.00541/full |
| _version_ | 1817996409717129216 |
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| author | Magnus Diller Rebecca Hasseli Marie-Lisa Hülser Iris Aykara Klaus Frommer Stefan Rehart Ulf Müller-Ladner Elena Neumann |
| author_facet | Magnus Diller Rebecca Hasseli Marie-Lisa Hülser Iris Aykara Klaus Frommer Stefan Rehart Ulf Müller-Ladner Elena Neumann |
| author_sort | Magnus Diller |
| collection | DOAJ |
| description | Background: Synovial fibroblasts (SF) play a major role in the pathogenesis of rheumatoid arthritis (RA) and develop an aggressive phenotype destroying cartilage and bone, thus termed RASF. JAK inhibitors have shown to be an efficient therapeutic option in RA treatment, but less is known about the effect of JAK inhibitors on activated RASF. The aim of the study was to examine the effects of JAK inhibitors on activated RASF.Methods: Synovium of RA patients was obtained during knee replacement surgeries. Synoviocytes were isolated and pretreated with JAK inhibitors. Pro-inflammatory cytokines and matrix degrading proteinases were measured by ELISA in supernatant after stimulation with oncostatin M or IL-1β. The proliferation of RASF was measured by BrdU incorporation. Cell culture inserts were used to evaluate cell migration. For adhesion assays, RASF were seeded in culture plates. Then, plates were extensively shaken and adherent RASF quantified. Cell viability, cytotoxicity and apoptosis were measured using the ApoTox-Glo™ Triplex and the CellTox™ Green Cytotoxicity Assay.Results: Tofacitinib and baricitinib decreased the IL-6 release of RASF stimulated with oncostatin M. JAK inhibition attenuated the IL-6 release of IL-1β activated and with soluble IL-6 receptor treated RASF. In contrast, only peficitinib and filgotinib decreased the IL-6 release of RASF activated with IL-1β. Peficitinib decreased also the MMP-3, CXCL8, and CXCL1 release at 5 μM. Moreover, peficitinib was the only JAK inhibitor suppressing proliferation of activated RASF at 1 μM. Peficitinib further decreased the migration of RASF without being cytotoxic or pro-apoptotic and without altering cell adhesion.Conclusions: JAK inhibitors effectively suppress the inflammatory response induced by oncostatin M and by transsignaling of IL-6 in RASF. Only peficitinib modulated the IL-1β-induced response of RASF and their proliferation in vitro at concentrations close to reported Cmax values of well tolerated doses in vivo. In contrast to filgotinib, peficitinib also highly suppressed RASF migration showing the potential of peficitinib to target RASF. |
| first_indexed | 2024-04-14T02:21:55Z |
| format | Article |
| id | doaj.art-51c0b9e14f4a4f2da436c17752c13252 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-14T02:21:55Z |
| publishDate | 2019-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-51c0b9e14f4a4f2da436c17752c132522022-12-22T02:17:59ZengFrontiers Media S.A.Frontiers in Immunology1664-32242019-03-011010.3389/fimmu.2019.00541441157Targeting Activated Synovial Fibroblasts in Rheumatoid Arthritis by PeficitinibMagnus Diller0Rebecca Hasseli1Marie-Lisa Hülser2Iris Aykara3Klaus Frommer4Stefan Rehart5Ulf Müller-Ladner6Elena Neumann7Department of Rheumatology and Clinical Immunology, Campus Kerckhoff, Justus-Liebig-University Giessen, Giessen, GermanyDepartment of Rheumatology and Clinical Immunology, Campus Kerckhoff, Justus-Liebig-University Giessen, Giessen, GermanyDepartment of Rheumatology and Clinical Immunology, Campus Kerckhoff, Justus-Liebig-University Giessen, Giessen, GermanyDepartment of Rheumatology and Clinical Immunology, Campus Kerckhoff, Justus-Liebig-University Giessen, Giessen, GermanyDepartment of Rheumatology and Clinical Immunology, Campus Kerckhoff, Justus-Liebig-University Giessen, Giessen, GermanyDepartment of Orthopedics and Trauma Surgery, Agaplesion Markus Hospital, Frankfurt, GermanyDepartment of Rheumatology and Clinical Immunology, Campus Kerckhoff, Justus-Liebig-University Giessen, Giessen, GermanyDepartment of Rheumatology and Clinical Immunology, Campus Kerckhoff, Justus-Liebig-University Giessen, Giessen, GermanyBackground: Synovial fibroblasts (SF) play a major role in the pathogenesis of rheumatoid arthritis (RA) and develop an aggressive phenotype destroying cartilage and bone, thus termed RASF. JAK inhibitors have shown to be an efficient therapeutic option in RA treatment, but less is known about the effect of JAK inhibitors on activated RASF. The aim of the study was to examine the effects of JAK inhibitors on activated RASF.Methods: Synovium of RA patients was obtained during knee replacement surgeries. Synoviocytes were isolated and pretreated with JAK inhibitors. Pro-inflammatory cytokines and matrix degrading proteinases were measured by ELISA in supernatant after stimulation with oncostatin M or IL-1β. The proliferation of RASF was measured by BrdU incorporation. Cell culture inserts were used to evaluate cell migration. For adhesion assays, RASF were seeded in culture plates. Then, plates were extensively shaken and adherent RASF quantified. Cell viability, cytotoxicity and apoptosis were measured using the ApoTox-Glo™ Triplex and the CellTox™ Green Cytotoxicity Assay.Results: Tofacitinib and baricitinib decreased the IL-6 release of RASF stimulated with oncostatin M. JAK inhibition attenuated the IL-6 release of IL-1β activated and with soluble IL-6 receptor treated RASF. In contrast, only peficitinib and filgotinib decreased the IL-6 release of RASF activated with IL-1β. Peficitinib decreased also the MMP-3, CXCL8, and CXCL1 release at 5 μM. Moreover, peficitinib was the only JAK inhibitor suppressing proliferation of activated RASF at 1 μM. Peficitinib further decreased the migration of RASF without being cytotoxic or pro-apoptotic and without altering cell adhesion.Conclusions: JAK inhibitors effectively suppress the inflammatory response induced by oncostatin M and by transsignaling of IL-6 in RASF. Only peficitinib modulated the IL-1β-induced response of RASF and their proliferation in vitro at concentrations close to reported Cmax values of well tolerated doses in vivo. In contrast to filgotinib, peficitinib also highly suppressed RASF migration showing the potential of peficitinib to target RASF.https://www.frontiersin.org/article/10.3389/fimmu.2019.00541/fullJAK inhibitionpeficitinibsynovial fibroblastrheumatoid arthritisIL-1β |
| spellingShingle | Magnus Diller Rebecca Hasseli Marie-Lisa Hülser Iris Aykara Klaus Frommer Stefan Rehart Ulf Müller-Ladner Elena Neumann Targeting Activated Synovial Fibroblasts in Rheumatoid Arthritis by Peficitinib Frontiers in Immunology JAK inhibition peficitinib synovial fibroblast rheumatoid arthritis IL-1β |
| title | Targeting Activated Synovial Fibroblasts in Rheumatoid Arthritis by Peficitinib |
| title_full | Targeting Activated Synovial Fibroblasts in Rheumatoid Arthritis by Peficitinib |
| title_fullStr | Targeting Activated Synovial Fibroblasts in Rheumatoid Arthritis by Peficitinib |
| title_full_unstemmed | Targeting Activated Synovial Fibroblasts in Rheumatoid Arthritis by Peficitinib |
| title_short | Targeting Activated Synovial Fibroblasts in Rheumatoid Arthritis by Peficitinib |
| title_sort | targeting activated synovial fibroblasts in rheumatoid arthritis by peficitinib |
| topic | JAK inhibition peficitinib synovial fibroblast rheumatoid arthritis IL-1β |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2019.00541/full |
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