title: Inhibition of PDE4B suppresses inflammation by increasing expression of the deubiquitinase CYLD.
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.
authors.affiliation: Center for Inflammation, Immunity & Infection and Department of Biology, Georgia State University, 100 Piedmont Avenue, Atlanta, Georgia 30303, USA.
authors.forename: Kensei
authors.initials: K
authors.lastname: Komatsu
authors.forename: Ji-Yun
authors.initials: JY
authors.lastname: Lee
authors.forename: Masanori
authors.initials: M
authors.lastname: Miyata
authors.forename: Jae
authors.initials: J
authors.lastname: Hyang Lim
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Jono
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Koga
authors.forename: Haidong
authors.initials: H
authors.lastname: Xu
authors.forename: Chen
authors.initials: C
authors.lastname: Yan
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Kai
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Li
mesh_terms: D002478:Cells, Cultured; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000187:drug effects*; D000074749:Deubiquitinating Enzyme CYLD; D015536:Down-Regulation; D004789:Enzyme Activation; D006801:Humans; D007249:Inflammation / Q000201:enzymology / Q000517:prevention & control*; D048056:Mitogen-Activated Protein Kinase 9 / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D010726:Phosphodiesterase Inhibitors; D025521:Tumor Suppressor Proteins; D048056:Mitogen-Activated Protein Kinase 9; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD