Il6/Sil6R Regulates Tnfα-Inflammatory Response In Synovial Fibroblasts Through Modulation of Transcriptional and Post-Transcriptional Mechanisms
| Autor: | Marina Romero, Yolanda Ruano, José L. Pablos, Francisco J. Blanco, Alicia Usategui, Cristina Municio, Alvaro Valin, Gabriel Criado, Jesús Fernández-Felipe, Juan D. Cañete, Manuel J. Del Rey |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Chemokine MMP1 Matrix metalloproteinase Arthritis Rheumatoid 0302 clinical medicine Cell Movement TNFα Chemokine CCL8 Cycloheximide skin and connective tissue diseases biology Chemistry lcsh:Cytology Soluble receptor Synovial Membrane JAK-STAT signaling pathway Cross-talk Cell biology STAT Transcription Factors Dactinomycin Cytokines Tumor necrosis factor alpha Chemokines Signal Transduction Research Article musculoskeletal diseases CCL2 Synovial fibroblast Peripheral blood mononuclear cell Cell Line 03 medical and health sciences Nitriles Humans Interleukin 8 lcsh:QH573-671 Rheumatoid arthritis Post-transcriptional mechanisms Molecular Biology Janus Kinases 030203 arthritis & rheumatology Inflammation Interleukin-6 Tumor Necrosis Factor-alpha Interleukin-8 Adalimumab Inflammatory response Cell Biology Transcriptional mechanisms Fibroblasts Receptors Interleukin-6 JAK/STAT Matrix Metalloproteinases IL6 Kinetics 030104 developmental biology Pyrimidines Gene Expression Regulation biology.protein Pyrazoles |
| Zdroj: | BMC Molecular and Cell Biology RUC. Repositorio da Universidade da Coruña instname BMC Molecular and Cell Biology, Vol 21, Iss 1, Pp 1-12 (2020) RUC: Repositorio da Universidade da Coruña Universidade da Coruña (UDC) |
| Popis: | Introduction 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 TNFα and IL6/sIL6R signaling to the effector pro-inflammatory response of SF. Methods SF lines were stimulated with either TNFα, 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 Results The stimulation of SF with IL6/sIL6R and TNFα, 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 TNFα 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 TNFα-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. |
| Databáze: | OpenAIRE |
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