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dc.contributor.authorDiller, Magnus
dc.contributor.authorHasseli, Rebecca
dc.contributor.authorHülser, Marie-Lisa
dc.contributor.authorAykara, Iris
dc.contributor.authorFrommer, Klaus
dc.contributor.authorRehart, Stefan
dc.contributor.authorMüller-Ladner, Ulf
dc.contributor.authorNeumann, Elena
dc.date.accessioned2022-11-18T09:55:16Z
dc.date.available2020-08-14T09:58:05Z
dc.date.available2022-11-18T09:55:16Z
dc.date.issued2019
dc.identifier.urihttp://nbn-resolving.de/urn:nbn:de:hebis:26-opus-153830
dc.identifier.urihttps://jlupub.ub.uni-giessen.de//handle/jlupub/9564
dc.identifier.urihttp://dx.doi.org/10.22029/jlupub-8952
dc.description.abstractBackground: 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-1beta. 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-1beta 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-1beta. Peficitinib decreased also the MMP-3, CXCL8, and CXCL1 release at 5 muM. Moreover, peficitinib was the only JAK inhibitor suppressing proliferation of activated RASF at 1 muM. 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-1beta-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.en
dc.language.isoende_DE
dc.rightsNamensnennung 4.0 International*
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/*
dc.subjectJAK inhibitionen
dc.subjectpeficitiniben
dc.subjectsynovial fibroblasten
dc.subjectrheumatoid arthritisen
dc.subjectIL-1betaen
dc.subject.ddcddc:610de_DE
dc.titleTargeting Activated Synovial Fibroblasts in Rheumatoid Arthritis by Peficitiniben
dc.typearticlede_DE
local.affiliationFB 11 - Medizinde_DE
local.opus.id15383
local.opus.instituteDepartment of Rheumatology and Clinical Immunologyde_DE
local.opus.fachgebietMedizinde_DE
local.source.urihttps://doi.org/10.3389/fimmu.2019.00541
local.source.freetextFrontiers in Immunology 10:541de_DE


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