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

Kensei Komatsu, Ji-Yun Lee, Masanori Miyata, Jae Hyang Lim, Hirofumi Jono, Tomoaki Koga, Haidong Xu, Chen Yan, Hirofumi Kai and Jian-Dong Li ()
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Kensei Komatsu: Center for Inflammation, Georgia State University
Ji-Yun Lee: Center for Inflammation, Georgia State University
Masanori Miyata: Center for Inflammation, Georgia State University
Jae Hyang Lim: Ewha Womans University School of Medicine
Hirofumi Jono: Graduate School of Pharmaceutical Sciences, Kumamoto University
Tomoaki Koga: Juntendo University School of Medicine
Haidong Xu: Center for Inflammation, Georgia State University
Chen Yan: University of Rochester Medical Center
Hirofumi Kai: Graduate School of Pharmaceutical Sciences, Kumamoto University
Jian-Dong Li: Center for Inflammation, Georgia State University

Nature Communications, 2013, vol. 4, issue 1, 1-13

Abstract: Abstract 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.

Date: 2013
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DOI: 10.1038/ncomms2674

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