ArticleProceedings of the National Academy of Sciences of the United States of America2015
Cross-talk between PKA-Cβ and p65 mediates synergistic induction of PDE4B by roflumilast and NTHi.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
26 citing papers in PubMed, 41 citations in OpenAlex.
- Pharmacokinetics of single- and multiple-dose roflumilast: an open-label, three-way crossover study in healthy Chinese volunteers.Drug design, development and therapy · 2018Trial
- Chenodeoxycholic acid restrains tumor growth via TGR5-dependent type 1 dendritic cells cross-priming.Signal transduction and targeted therapy · 2026Article
- Identification of PANoptosis hub genes driving immune activation and tubulointerstitial injury in diabetic kidney disease by integrative bioinformatics and machine learning.Frontiers in immunology · 2026Article
- Posttranslational modifications of phosphodiesterase type 4 enzymes represent novel points for therapeutic targeting.The FEBS journal · 2025Review
- Targeted protein degradation of PDE4 shortforms by a novel proteolysis targeting chimera.The FEBS journal · 2025Article
- Cyclic nucleotide phosphodiesterases as drug targets.Pharmacological reviews · 2025Review
- The multifaceted role of phosphodiesterase 4 in tumor: from tumorigenesis to immunotherapy.Frontiers in immunology · 2025Review
- Microglial circDlg1 modulates neuroinflammation by blocking PDE4B ubiquitination-dependent degradation associated with Alzheimer's disease.Theranostics · 2025Article
- Phosphodiesterase 4D activity in acrodysostosis-associated neural pathology: too much or too little?Brain communications · 2024Review
- IgG immune complex-induced acute lung injury is ameliorated by cAMP via down-regulation of C/EBP- and AP-1-mediated transcriptions.Journal of inflammation (London, England) · 2023Article
- Negative Cross-Talk between TLR2/4-Independent AMPKα1 and TLR2/4-Dependent JNK RegulatesJournal of immunology (Baltimore, Md. : 1950) · 2022Article
- Phosphodiesterase 10A Is a Key Mediator of Lung Inflammation.Journal of immunology (Baltimore, Md. : 1950) · 2021Article
- The cAMP-phosphodiesterase 4 (PDE4) controls β-adrenoceptor- and CFTR-dependent saliva secretion in mice.The Biochemical journal · 2021Article
- Vinpocetine SuppressesJournal of immunology (Baltimore, Md. : 1950) · 2020Article
- Inhibition of TPL2 by interferon-α suppresses bladder cancer through activation of PDE4D.Journal of experimental & clinical cancer research : CR · 2018Article
- Dexamethasone Inhibits Synergistic Induction of PDE4B Expression by Roflumilast and Bacterium NTHi.International journal of molecular sciences · 2018Article
- The Molecular Basis for Specificity at the Level of the Protein Kinase a Catalytic Subunit.Frontiers in endocrinology · 2018Review
- Resveratrol therapeutics combines both antimicrobial and immunomodulatory properties against respiratory infection by nontypeable Haemophilus influenzae.Scientific reports · 2017Article
- Roflumilast reverses polymicrobial sepsis-induced liver damage by inhibiting inflammation in mice.Laboratory investigation; a journal of technical methods and pathology · 2017Article
- Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
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.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.