Interleukin-1beta induced activation of nuclear factor-kappab can be inhibited by novel pharmacological agents in osteoarthritis
| Autor: | Sarah Nicol Lauder, Sara Madelaine Carty, R. J. Hill, C. E. Carpenter, Anwen Sian Williams, Jan Bondeson, P. Brennan, F. Talamas |
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| Rok vydání: | 2007 |
| Předmět: |
medicine.medical_treatment
Interleukin-1beta Electrophoretic Mobility Shift Assay Enzyme-Linked Immunosorbent Assay Matrix metalloproteinase Pharmacology Receptors Tumor Necrosis Factor Etanercept Rheumatology Osteoarthritis medicine Humans Pharmacology (medical) Viability assay Receptor Interleukin 6 Cells Cultured biology business.industry Interleukin-6 Synovial Membrane NF-kappa B Interleukin Coculture Techniques medicine.anatomical_structure Cytokine Antirheumatic Agents Immunoglobulin G Immunology biology.protein Tumor necrosis factor alpha Matrix Metalloproteinase 3 Synovial membrane Matrix Metalloproteinase 1 business Signal Transduction |
| Zdroj: | Rheumatology (Oxford, England). 46(5) |
| ISSN: | 1462-0324 |
| Popis: | To investigate the importance of activation of the transcription factor, nuclear factor-kappaB (NF-kappaB) by interleukin-1beta (IL-1beta) and tumour necrosis factor-alpha (TNF-alpha) in the pathogenesis of osteoarthritis (OA) and assess its suitability as a target for therapy by determining its role in the induction of the cytokine IL-6 and the degenerative enzymes, matrix metalloproteinase (MMP)-1 and MMP-3 in vitro.Three distinct cellular models, derived from primary OA tissue, were employed, namely, fibroblast-like synoviocytes (OA-SF); co-cultures containing phenotypic macrophage-like and fibroblast-like cells (OA-COCUL); and primary OA synovial tissue explants (OA-EXP). These were treated with specific inhibitors of IL-1beta, TNF-alpha and NF-kappaB to assess their differential role in the production of pathologically relevant mediators, specifically IL-6, MMP-1, MMP-3 and the tissue inhibitor of metalloproteinases-1 (TIMP-1), which were quantified by enzyme-linked immunosorbent assay.Inhibition of NF-kappaB by a novel agent, RO100 at a dose of 0.1 microM, exerted significant (P0.05) repression of IL-6, MMP-1 and MMP-3 production in OA-SF. Notably, neither TIMP-1 production nor cell viability was significantly affected at the dose tested. These data were reproduced in OA-EXP, which might be considered as having greater physiological relevance. Interestingly, comparable efficacy was noted using IL-1beta and TNF-alpha neutralizing antibodies in OA-COCUL.We have demonstrated that a novel pharmacological inhibitor of NF-kappaB, RO100 inhibits pathological mediators of OA progression with equivalent efficacy as established IL-1beta and TNF-alpha neutralizing strategies. Our findings highlight a potential for developing NF-kappaB targeted therapeutics for positively regulating disease activity and improving clinical outcome in OA. |
| Databáze: | OpenAIRE |
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