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Inhibition of PDE4B suppresses inflammation by increasing expression of the deubiquitinase CYLD

The deubiquitinase CYLD acts as a key negative regulator to tightly control overactive inflammation. Most anti-inflammatory strategies have focused on directly targeting the positive regulator, which often results in significant side effects such as suppression of the host defence response. Here, we...

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Autores principales: Komatsu, Kensei, Lee, Ji-Yun, Miyata, Masanori, Hyang Lim, Jae, Jono, Hirofumi, Koga, Tomoaki, Xu, Haidong, Yan, Chen, Kai, Hirofumi, Li, Jian-Dong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Pub. Group 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3644066/
https://www.ncbi.nlm.nih.gov/pubmed/23575688
http://dx.doi.org/10.1038/ncomms2674
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author Komatsu, Kensei
Lee, Ji-Yun
Miyata, Masanori
Hyang Lim, Jae
Jono, Hirofumi
Koga, Tomoaki
Xu, Haidong
Yan, Chen
Kai, Hirofumi
Li, Jian-Dong
author_facet Komatsu, Kensei
Lee, Ji-Yun
Miyata, Masanori
Hyang Lim, Jae
Jono, Hirofumi
Koga, Tomoaki
Xu, Haidong
Yan, Chen
Kai, Hirofumi
Li, Jian-Dong
author_sort Komatsu, Kensei
collection PubMed
description The deubiquitinase CYLD acts as a key negative regulator to tightly control overactive inflammation. Most anti-inflammatory strategies have focused on directly targeting the positive regulator, which often results in significant side effects such as suppression of the host defence response. Here, we show that inhibition of phosphodiesterase 4B (PDE4B) markedly enhances upregulation of CYLD expression in response to bacteria, thereby suggesting that PDE4B acts as a negative regulator for CYLD. Interestingly, in Cyld-deficient mice, inhibition of PDE4B no longer suppresses inflammation. Moreover, PDE4B negatively regulates CYLD via specific activation of JNK2 but not JNK1. Importantly, ototopical post-inoculation administration of a PDE4 inhibitor suppresses inflammation in this animal model, thus demonstrating the therapeutic potential of targeting PDE4. These studies provide insights into how inflammation is tightly regulated via the inhibition of its negative regulator and may also lead to the development of new anti-inflammatory therapeutics that upregulate CYLD expression.
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spelling pubmed-36440662013-05-17 Inhibition of PDE4B suppresses inflammation by increasing expression of the deubiquitinase CYLD Komatsu, Kensei Lee, Ji-Yun Miyata, Masanori Hyang Lim, Jae Jono, Hirofumi Koga, Tomoaki Xu, Haidong Yan, Chen Kai, Hirofumi Li, Jian-Dong Nat Commun Article The deubiquitinase CYLD acts as a key negative regulator to tightly control overactive inflammation. Most anti-inflammatory strategies have focused on directly targeting the positive regulator, which often results in significant side effects such as suppression of the host defence response. Here, we show that inhibition of phosphodiesterase 4B (PDE4B) markedly enhances upregulation of CYLD expression in response to bacteria, thereby suggesting that PDE4B acts as a negative regulator for CYLD. Interestingly, in Cyld-deficient mice, inhibition of PDE4B no longer suppresses inflammation. Moreover, PDE4B negatively regulates CYLD via specific activation of JNK2 but not JNK1. Importantly, ototopical post-inoculation administration of a PDE4 inhibitor suppresses inflammation in this animal model, thus demonstrating the therapeutic potential of targeting PDE4. These studies provide insights into how inflammation is tightly regulated via the inhibition of its negative regulator and may also lead to the development of new anti-inflammatory therapeutics that upregulate CYLD expression. Nature Pub. Group 2013-04-09 /pmc/articles/PMC3644066/ /pubmed/23575688 http://dx.doi.org/10.1038/ncomms2674 Text en Copyright © 2013, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. http://creativecommons.org/licenses/by-nc-nd/3.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/
spellingShingle Article
Komatsu, Kensei
Lee, Ji-Yun
Miyata, Masanori
Hyang Lim, Jae
Jono, Hirofumi
Koga, Tomoaki
Xu, Haidong
Yan, Chen
Kai, Hirofumi
Li, Jian-Dong
Inhibition of PDE4B suppresses inflammation by increasing expression of the deubiquitinase CYLD
title Inhibition of PDE4B suppresses inflammation by increasing expression of the deubiquitinase CYLD
title_full Inhibition of PDE4B suppresses inflammation by increasing expression of the deubiquitinase CYLD
title_fullStr Inhibition of PDE4B suppresses inflammation by increasing expression of the deubiquitinase CYLD
title_full_unstemmed Inhibition of PDE4B suppresses inflammation by increasing expression of the deubiquitinase CYLD
title_short Inhibition of PDE4B suppresses inflammation by increasing expression of the deubiquitinase CYLD
title_sort inhibition of pde4b suppresses inflammation by increasing expression of the deubiquitinase cyld
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3644066/
https://www.ncbi.nlm.nih.gov/pubmed/23575688
http://dx.doi.org/10.1038/ncomms2674
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