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Inhibition of CDK9 as a therapeutic strategy for inflammatory arthritis

Rheumatoid arthritis is characterised by synovial inflammation and proliferation of fibroblast-like synoviocytes. The induction of apoptosis has long been proposed as a target for proliferative autoimmune diseases, and has further been shown to act as a successful treatment of experimental models of...

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Autores principales: Hellvard, Annelie, Zeitlmann, Lutz, Heiser, Ulrich, Kehlen, Astrid, Niestroj, André, Demuth, Hans-Ulrich, Koziel, Joanna, Delaleu, Nicolas, Jan Potempa, Mydel, Piotr
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4980610/
https://www.ncbi.nlm.nih.gov/pubmed/27511630
http://dx.doi.org/10.1038/srep31441
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author Hellvard, Annelie
Zeitlmann, Lutz
Heiser, Ulrich
Kehlen, Astrid
Niestroj, André
Demuth, Hans-Ulrich
Koziel, Joanna
Delaleu, Nicolas
Jan Potempa,
Mydel, Piotr
author_facet Hellvard, Annelie
Zeitlmann, Lutz
Heiser, Ulrich
Kehlen, Astrid
Niestroj, André
Demuth, Hans-Ulrich
Koziel, Joanna
Delaleu, Nicolas
Jan Potempa,
Mydel, Piotr
author_sort Hellvard, Annelie
collection PubMed
description Rheumatoid arthritis is characterised by synovial inflammation and proliferation of fibroblast-like synoviocytes. The induction of apoptosis has long been proposed as a target for proliferative autoimmune diseases, and has further been shown to act as a successful treatment of experimental models of arthritis, such as collagen-induced arthritis. Here we examined the effects of specific oral small-molecule inhibitors of the transcription regulating cyclin-dependent kinase 9 on the development and progression of collagen-induced arthritis. DBA/1 mice were immunised with bovine collagen type II and treated orally with specific CDK9 inhibitors. The effects of CDK9 inhibition on RNA levels and protein expression, apoptosis induction, caspase activation and lymphocyte phenotype were further analysed. Mice showed a significant delay in disease onset and a reduction in disease severity following treatment with CDK9 inhibitors. Inhibiting CDK9 activity in peripheral blood mononuclear cells resulted in the loss of Mcl-1 expression at both the protein and RNA levels, along with a subsequent increase in apoptosis. CDK9 specific inhibitors may be a potential alternative treatment not only of cancer, but also for autoimmune- and inflammatory diseases. Taken together, these results show that transient inhibition of CDK9 induces apoptosis in leukocyte subsets and modulates the immune response.
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spelling pubmed-49806102016-08-19 Inhibition of CDK9 as a therapeutic strategy for inflammatory arthritis Hellvard, Annelie Zeitlmann, Lutz Heiser, Ulrich Kehlen, Astrid Niestroj, André Demuth, Hans-Ulrich Koziel, Joanna Delaleu, Nicolas Jan Potempa, Mydel, Piotr Sci Rep Article Rheumatoid arthritis is characterised by synovial inflammation and proliferation of fibroblast-like synoviocytes. The induction of apoptosis has long been proposed as a target for proliferative autoimmune diseases, and has further been shown to act as a successful treatment of experimental models of arthritis, such as collagen-induced arthritis. Here we examined the effects of specific oral small-molecule inhibitors of the transcription regulating cyclin-dependent kinase 9 on the development and progression of collagen-induced arthritis. DBA/1 mice were immunised with bovine collagen type II and treated orally with specific CDK9 inhibitors. The effects of CDK9 inhibition on RNA levels and protein expression, apoptosis induction, caspase activation and lymphocyte phenotype were further analysed. Mice showed a significant delay in disease onset and a reduction in disease severity following treatment with CDK9 inhibitors. Inhibiting CDK9 activity in peripheral blood mononuclear cells resulted in the loss of Mcl-1 expression at both the protein and RNA levels, along with a subsequent increase in apoptosis. CDK9 specific inhibitors may be a potential alternative treatment not only of cancer, but also for autoimmune- and inflammatory diseases. Taken together, these results show that transient inhibition of CDK9 induces apoptosis in leukocyte subsets and modulates the immune response. Nature Publishing Group 2016-08-11 /pmc/articles/PMC4980610/ /pubmed/27511630 http://dx.doi.org/10.1038/srep31441 Text en Copyright © 2016, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Hellvard, Annelie
Zeitlmann, Lutz
Heiser, Ulrich
Kehlen, Astrid
Niestroj, André
Demuth, Hans-Ulrich
Koziel, Joanna
Delaleu, Nicolas
Jan Potempa,
Mydel, Piotr
Inhibition of CDK9 as a therapeutic strategy for inflammatory arthritis
title Inhibition of CDK9 as a therapeutic strategy for inflammatory arthritis
title_full Inhibition of CDK9 as a therapeutic strategy for inflammatory arthritis
title_fullStr Inhibition of CDK9 as a therapeutic strategy for inflammatory arthritis
title_full_unstemmed Inhibition of CDK9 as a therapeutic strategy for inflammatory arthritis
title_short Inhibition of CDK9 as a therapeutic strategy for inflammatory arthritis
title_sort inhibition of cdk9 as a therapeutic strategy for inflammatory arthritis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4980610/
https://www.ncbi.nlm.nih.gov/pubmed/27511630
http://dx.doi.org/10.1038/srep31441
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