title: Cross-talk between PKA-Cβ and p65 mediates synergistic induction of PDE4B by roflumilast and NTHi.
abstract: Phosphodiesterase 4B (PDE4B) plays a key role in regulating inflammation. Roflumilast, a phosphodiesterase (PDE)4-selective inhibitor, has recently been approved for treating severe chronic obstructive pulmonary disease (COPD) patients with exacerbation. However, there is also clinical evidence suggesting the development of tachyphylaxis or tolerance on repeated dosing of roflumilast and the possible contribution of PDE4B up-regulation, which could be counterproductive for suppressing inflammation. Thus, understanding how PDE4B is up-regulated in the context of the complex pathogenesis and medications of COPD may help improve the efficacy and possibly ameliorate the tolerance of roflumilast. Here we show that roflumilast synergizes with nontypeable Haemophilus influenzae (NTHi), a major bacterial cause of COPD exacerbation, to up-regulate PDE4B2 expression in human airway epithelial cells in vitro and in vivo. Up-regulated PDE4B2 contributes to the induction of certain important chemokines in both enzymatic activity-dependent and activity-independent manners. We also found that protein kinase A catalytic subunit β (PKA-Cβ) and nuclear factor-κB (NF-κB) p65 subunit were required for the synergistic induction of PDE4B2. PKA-Cβ phosphorylates p65 in a cAMP-dependent manner. Moreover, Ser276 of p65 is critical for mediating the PKA-Cβ-induced p65 phosphorylation and the synergistic induction of PDE4B2. Collectively, our data unveil a previously unidentified mechanism underlying synergistic up-regulation of PDE4B2 via a cross-talk between PKA-Cβ and p65 and may help develop new therapeutic strategies to improve the efficacy of PDE4 inhibitor.
authors.affiliation: Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30302;
authors.forename: Seiko
authors.initials: S
authors.lastname: Susuki-Miyata
authors.affiliation: Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30302;
authors.forename: Masanori
authors.initials: M
authors.lastname: Miyata
authors.affiliation: Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30302;
authors.forename: Byung-Cheol
authors.initials: BC
authors.lastname: Lee
authors.affiliation: Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30302;
authors.forename: Haidong
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan; and.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Kai
authors.affiliation: Aab Cardiovascular Research Institute, University of Rochester Medical Center, Rochester, NY 14642 jdli@gsu.edu chen_yan@urmc.rochester.edu.
authors.forename: Chen
authors.initials: C
authors.lastname: Yan
authors.affiliation: Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30302; jdli@gsu.edu chen_yan@urmc.rochester.edu.
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Li
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D020134:Catalytic Domain; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / Q000378:metabolism*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism*; D003521:Cyclopropanes / Q000494:pharmacology; D006193:Haemophilus influenzae; D006801:Humans; D007249:Inflammation; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D011485:Protein Binding; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy*; D034741:RNA, Small Interfering / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D000631:Aminopyridines; D001549:Benzamides; D003521:Cyclopropanes; C498143:RELA protein, human; D034741:RNA, Small Interfering; D051996:Transcription Factor RelA; C424423:Roflumilast; D000242:Cyclic AMP; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits; C463959:protein kinase A Calpha; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517360:PDE4B protein, human
keywords: PDE4B; PKA-Cβ; Roflumilast; nontypeable Haemophilus influenzae; p65
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