Smac127 Has Proapoptotic and Anti-Inflammatory Effects on Rheumatoid Arthritis Fibroblast-Like Synoviocytes
Rheumatoid arthritis (RA) is characterized by synovial inflammation and hyperplasia. Fibroblast-like synoviocytes (FLSs) are apoptosis-resistant and contribute to the pathogenesis of RA by producing cytokines and proteolytic enzymes, which degrade the extracellular matrix. We evaluated the proapopto...
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| Format: | Article |
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Wiley
2016-01-01
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| Series: | Mediators of Inflammation |
| Online Access: | http://dx.doi.org/10.1155/2016/6905678 |
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| author | D. Lattuada R. Gualtierotti K. Crotta P. Seneci F. Ingegnoli C. Corradini R. Viganò O. Marelli C. Casnici |
| author_facet | D. Lattuada R. Gualtierotti K. Crotta P. Seneci F. Ingegnoli C. Corradini R. Viganò O. Marelli C. Casnici |
| author_sort | D. Lattuada |
| collection | DOAJ |
| description | Rheumatoid arthritis (RA) is characterized by synovial inflammation and hyperplasia. Fibroblast-like synoviocytes (FLSs) are apoptosis-resistant and contribute to the pathogenesis of RA by producing cytokines and proteolytic enzymes, which degrade the extracellular matrix. We evaluated the proapoptotic and anti-inflammatory activity of the small molecule Smac127 on RA-FLSs cultured in synovial fluid (SF), in order to reproduce the physiopathological environmental characteristic of RA joints. In this context, Smac127 induces apoptosis by inhibiting apoptosis proteins (IAPs). This inhibition activates caspase 3 and restores the apoptotic pathway. In addition, Smac127 induces a significant inhibition of the secretion of IL-15 and IL-6, stimulation of pannus formation, and damage of bone and cartilage in RA. Also the secretion of the anti-inflammatory cytokine IL-10 is dramatically increased in the presence of Smac127. The cartilage destruction in RA patients is partly mediated by metalloproteinases; here we show that the MMP-1 production by fibroblasts cultured in SF is significantly antagonized by Smac127. Conversely, this molecule has no significant effects on RANKL and OPG production. Our observations demonstrate that Smac127 has beneficial regulatory effects on inflammatory state of RA-FLSs and suggest a potential use of Smac127 for the control of inflammation and disease progression in RA. |
| format | Article |
| id | doaj-art-f44a73d651a04f679ddbd7b3d0a0b6d2 |
| institution | Kabale University |
| issn | 0962-9351 1466-1861 |
| language | English |
| publishDate | 2016-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Mediators of Inflammation |
| spelling | doaj-art-f44a73d651a04f679ddbd7b3d0a0b6d22025-02-03T01:08:50ZengWileyMediators of Inflammation0962-93511466-18612016-01-01201610.1155/2016/69056786905678Smac127 Has Proapoptotic and Anti-Inflammatory Effects on Rheumatoid Arthritis Fibroblast-Like SynoviocytesD. Lattuada0R. Gualtierotti1K. Crotta2P. Seneci3F. Ingegnoli4C. Corradini5R. Viganò6O. Marelli7C. Casnici8Department of Medical Biotechnology and Translational Medicine, School of Medicine, University of Milan, 20129 Milan, ItalyDivision of Rheumatology, A.O. Institute of Gaetano Pini, Department of Clinical Sciences & Community Health, University of Milan, 20122 Milan, ItalyDepartment of Medical Biotechnology and Translational Medicine, School of Medicine, University of Milan, 20129 Milan, ItalyDepartment of Chemistry, University of Milan, 20129 Milan, ItalyDivision of Rheumatology, A.O. Institute of Gaetano Pini, Department of Clinical Sciences & Community Health, University of Milan, 20122 Milan, ItalyDepartment of Biomedical, Surgical and Dental Sciences, University of Milan c/o Ist Division of Orthopaedy and Traumatology, A.O. Institute of Gaetano Pini, 20112 Milan, ItalyDepartment of Physiatry and Rheumatology, Chief of Centre for Rheumatoid Arthritis, A.O. Institute Gaetano Pini, 20122 Milan, ItalyDepartment of Medical Biotechnology and Translational Medicine, School of Medicine, University of Milan, 20129 Milan, ItalyDepartment of Medical Biotechnology and Translational Medicine, School of Medicine, University of Milan, 20129 Milan, ItalyRheumatoid arthritis (RA) is characterized by synovial inflammation and hyperplasia. Fibroblast-like synoviocytes (FLSs) are apoptosis-resistant and contribute to the pathogenesis of RA by producing cytokines and proteolytic enzymes, which degrade the extracellular matrix. We evaluated the proapoptotic and anti-inflammatory activity of the small molecule Smac127 on RA-FLSs cultured in synovial fluid (SF), in order to reproduce the physiopathological environmental characteristic of RA joints. In this context, Smac127 induces apoptosis by inhibiting apoptosis proteins (IAPs). This inhibition activates caspase 3 and restores the apoptotic pathway. In addition, Smac127 induces a significant inhibition of the secretion of IL-15 and IL-6, stimulation of pannus formation, and damage of bone and cartilage in RA. Also the secretion of the anti-inflammatory cytokine IL-10 is dramatically increased in the presence of Smac127. The cartilage destruction in RA patients is partly mediated by metalloproteinases; here we show that the MMP-1 production by fibroblasts cultured in SF is significantly antagonized by Smac127. Conversely, this molecule has no significant effects on RANKL and OPG production. Our observations demonstrate that Smac127 has beneficial regulatory effects on inflammatory state of RA-FLSs and suggest a potential use of Smac127 for the control of inflammation and disease progression in RA.http://dx.doi.org/10.1155/2016/6905678 |
| spellingShingle | D. Lattuada R. Gualtierotti K. Crotta P. Seneci F. Ingegnoli C. Corradini R. Viganò O. Marelli C. Casnici Smac127 Has Proapoptotic and Anti-Inflammatory Effects on Rheumatoid Arthritis Fibroblast-Like Synoviocytes Mediators of Inflammation |
| title | Smac127 Has Proapoptotic and Anti-Inflammatory Effects on Rheumatoid Arthritis Fibroblast-Like Synoviocytes |
| title_full | Smac127 Has Proapoptotic and Anti-Inflammatory Effects on Rheumatoid Arthritis Fibroblast-Like Synoviocytes |
| title_fullStr | Smac127 Has Proapoptotic and Anti-Inflammatory Effects on Rheumatoid Arthritis Fibroblast-Like Synoviocytes |
| title_full_unstemmed | Smac127 Has Proapoptotic and Anti-Inflammatory Effects on Rheumatoid Arthritis Fibroblast-Like Synoviocytes |
| title_short | Smac127 Has Proapoptotic and Anti-Inflammatory Effects on Rheumatoid Arthritis Fibroblast-Like Synoviocytes |
| title_sort | smac127 has proapoptotic and anti inflammatory effects on rheumatoid arthritis fibroblast like synoviocytes |
| url | http://dx.doi.org/10.1155/2016/6905678 |
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