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, Jian Dong Li

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49 Scopus citations


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.

Original languageEnglish
Article number1684
JournalNature Communications
StatePublished - 2013

Bibliographical note

Funding Information:
We thank Wenzhuo Y. Wang for her assistance with editing this manuscript. J.-D.L. is a Georgia Research Alliance Eminent Scholar. This work was supported by grants from National Institutes of Health DC005843 and DC004562 to J.-D.L.


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