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dc.contributor.authorValin, Alvaro
dc.contributor.authorDel Rey, Manuel J
dc.contributor.authorMunicio, Cristina
dc.contributor.authorUsategui, Alicia
dc.contributor.authorRomero, Marina
dc.contributor.authorFernández-Felipe, Jesús
dc.contributor.authorCañete, Juan D
dc.contributor.authorBLANCO GARCIA, FRANCISCO JAVIER 
dc.contributor.authorRuano, Yolanda
dc.contributor.authorCriado, Gabriel
dc.contributor.authorPablos, José L
dc.date.accessioned2022-03-16T08:37:11Z
dc.date.available2022-03-16T08:37:11Z
dc.date.issued2020
dc.identifier.issn2661-8850
dc.identifier.otherhttps://www.ncbi.nlm.nih.gov/pubmed/33126846es
dc.identifier.urihttp://hdl.handle.net/20.500.11940/16251
dc.description.abstractINTRODUCTION: The clinical efficacy of specific interleukin-6 inhibitors has confirmed the central role of IL6 in rheumatoid arthritis (RA). However the local role of IL6, in particular in synovial fibroblasts (SF) as a direct cellular target to IL6/sIL6R signal is not well characterized. The purpose of the study was to characterize the crosstalk between TNFalpha and IL6/sIL6R signaling to the effector pro-inflammatory response of SF. METHODS: SF lines were stimulated with either TNFalpha, IL6/sIL6R, or both together, for the time and dose indicated for each experiment, and where indicated, cells were treated with inhibitors actinomycin D, adalimumab, ruxolitinib and cycloheximide. mRNA expression of cytokines, chemokines and matrix metalloproteases (MMPs) were analyzed by quantitative RT-PCR. Level of IL8/CXCL8 and CCL8 in culture supernatants was measured by ELISA. Mononuclear and polymorphonuclear cells migration assays were assessed by transwell using conditioned medium from SF cultures. Statistical analyses were performed as indicated in the corresponding figure legends and a p-value < 0.05 was considered statistically significant. RESULTS: The stimulation of SF with IL6/sIL6R and TNFalpha, cooperatively promotes the expression of mono- and lymphocytic chemokines such as IL6, CCL8 and CCL2, as well as matrix degrading enzymes such as MMP1, while inhibiting the induction of central neutrophil chemokines such as IL8/CXCL8. These changes in the pattern of chemokines expression resulted in reduced polymorphonuclear (PMN) and increased mononuclear cells (MNC) chemoattraction by SF. Mechanistic analyses of the temporal expression of genes demonstrated that the cooperative regulation mediated by these two factors is mostly induced through de novo transcriptional mechanisms activated by IL6/sIL6R. Furthermore, we also demonstrate that TNFalpha and IL6/sIL6R cooperation is partially mediated by the expression of secondary factors signaling through JAK/STAT pathways. CONCLUSIONS: These results point out to a highly orchestrated response to IL6 in TNFalpha-induced SF and provide additional insights into the role of IL6/sIL6R in the context of RA, highlighting the contribution of IL6/sIL6R to the interplay of SF with other inflammatory cells.en
dc.rightsAtribución 4.0 Internacional
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subject.meshCytokines *
dc.subject.meshInterleukin-8 *
dc.subject.meshChemokines *
dc.subject.meshSTAT Transcription Factors *
dc.subject.meshSynovial Membrane *
dc.subject.meshSignal Transduction *
dc.subject.meshArthritis *
dc.subject.meshInterleukin-6 *
dc.subject.meshCycloheximide *
dc.subject.meshTumor Necrosis Factor-alpha *
dc.subject.meshPyrimidines *
dc.subject.meshChemokine CCL8 *
dc.subject.meshDactinomycin *
dc.subject.meshCell Line *
dc.subject.meshHumans *
dc.subject.meshPyrazoles *
dc.subject.meshFibroblasts *
dc.subject.meshCell Movement *
dc.subject.meshKinetics *
dc.subject.meshJanus Kinases *
dc.subject.meshGene Expression Regulation *
dc.subject.meshMatrix Metalloproteinases *
dc.subject.meshNitriles *
dc.subject.meshInflammation *
dc.titleIL6/sIL6R regulates TNF?-inflammatory response in synovial fibroblasts through modulation of transcriptional and post-transcriptional mechanismsen
dc.typeJournal Articlees
dc.authorsophosValin, Alvaro;Del Rey, Manuel J;Municio, Cristina;Usategui, Alicia;Romero, Marina;Fernández-Felipe, Jesús;Cañete, Juan D;Blanco, Francisco J;Ruano, Yolanda;Criado, Gabriel;Pablos, José L
dc.identifier.doi10.1186/s12860-020-00317-7
dc.identifier.pmid33126846
dc.identifier.sophos36069
dc.issue.number1es
dc.journal.titleBMC Molecular and Cell Biologyes
dc.organizationServizo Galego de Saúde::Estrutura de Xestión Integrada (EOXI)::Instituto de Investigación Biomédica da Coruña (INIBIC)es
dc.rights.accessRightsopenAccess
dc.subject.decsquimiocina CCL8 *
dc.subject.decsinterleucina-6 *
dc.subject.decsmembrana sinovial *
dc.subject.decsdactinomicina *
dc.subject.decscitocinas *
dc.subject.decsfactor de necrosis tumoral alfa *
dc.subject.decsfactores de transcripción STAT *
dc.subject.decspirimidinas *
dc.subject.decscinética *
dc.subject.decsquimiocinas *
dc.subject.decsregulación de la expresión génica *
dc.subject.decsinflamación *
dc.subject.decstransducción de señales *
dc.subject.decsinterleucina-8 *
dc.subject.decspirazoles *
dc.subject.decsnitrilos *
dc.subject.decsfibroblastos *
dc.subject.decscicloheximida *
dc.subject.decslínea celular *
dc.subject.decsmovimiento celular *
dc.subject.decshumanos *
dc.subject.decsmetaloproteinasas de la matriz *
dc.subject.decscinasas Janus *
dc.subject.decsartritis *
dc.subject.keywordINIBICes
dc.typefidesArtículo Originales
dc.typesophosArtículo Originales
dc.volume.number21es


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Atribución 4.0 Internacional
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