ArticleArthritis research & therapy2015
Apremilast, a novel phosphodiesterase 4 (PDE4) inhibitor, regulates inflammation through multiple cAMP downstream effectors.
Article in Arthritis research & therapy, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 83 citations in OpenAlex.
- Apremilast and narrowband ultraviolet B combination therapy suppresses Th17 axis and promotes melanogenesis in vitiligo skin: a randomized, split-body, pilot study in skin types IV-VI.Archives of dermatological research · 2023Trial
- Characterization of LY2775240, a selective phosphodiesterase-4 inhibitor, in nonclinical models and in healthy subjects.Clinical and translational science · 2021Trial
- The efficacy and safety of apremilast, etanercept and placebo in patients with moderate-to-severe plaque psoriasis: 52-week results from a phase IIIb, randomized, placebo-controlled trial (LIBERATE).Journal of the European Academy of Dermatology and Venereology : JEADV · 2017Trial
- Large-scale comparative virtual screening identifies novel molecular targets underlying the multi-target activity of quercetin in psoriasis.Inflammopharmacology · 2026Article
- Exploring biomarkers for treatment response in psoriatic arthritis: a focus on multi-omics technologies.The pharmacogenomics journal · 2026Review
- Peptide hormones and bile acids shaping immune tolerance of the liver: implications and applications.Protein & cell · 2026Review
- Identification and Validation of Key Purine Metabolism-Related Genes in Ulcerative Colitis Using Bioinformatics and Machine Learning.Journal of inflammation research · 2026Article
- Balancing efficacy and hepatotoxicity: a comprehensive review of oral medications in psoriasis management.Naunyn-Schmiedeberg's archives of pharmacology · 2025Review
- Discovery of a PDE4B and PDE4D selective bifunctional degrader for management of chronic inflammatory disorders.Journal of translational autoimmunity · 2025Article
- Comprehensive computational strategies for multi-target drug discovery in inflammatory bowel disease utilizing bioactive compounds.Scientific reports · 2025Article
- Oral Prednisolone, Apremilast and Human Umbilical Cord Mesenchymal Stem Cells in the Management of Pemphigus Foliaceus.Journal of inflammation research · 2025Article
- Apremilast in osteoarthritis: exploring its therapeutic mechanisms.Drugs in context · 2025Review
- Neutrophils in Atopic Dermatitis.Clinical reviews in allergy & immunology · 2024Review
- The PDE4 inhibitor apremilast modulates ethanol responses in Gabrb1-S409A knock-in mice via PKA-dependent and independent mechanisms.Neuropharmacology · 2024Article
- Anti-Inflammatory Effects of miR-369-3p via PDE4B in Intestinal Inflammatory Response.International journal of molecular sciences · 2024Article
- Targeting PDE4 as a promising therapeutic strategy in chronic ulcerative colitis through modulating mucosal homeostasis.Acta pharmaceutica Sinica. B · 2022Article
- Gut probiotic Lactobacillus rhamnosus attenuates PDE4B-mediated interleukin-6 induced by SARS-CoV-2 membrane glycoprotein.The Journal of nutritional biochemistry · 2021Article
- The Involvement of PDE4 in the Protective Effects of Melatonin on Cigarette-Smoke-Induced Chronic Obstructive Pulmonary Disease.Molecules (Basel, Switzerland) · 2021Article
- Article
- Therapeutic Development Based on the Immunopathogenic Mechanisms of Psoriasis.Pharmaceutics · 2021Review
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
introductionThis work was undertaken to delineate intracellular signaling pathways for the PDE4 inhibitor apremilast and to examine interactions between apremilast, methotrexate and adenosine A2A receptors (A2AR).
methodsAfter apremilast and LPS incubation, intracellular cAMP, TNF-α, IL-10, IL-6 and IL-1α were measured in the Raw264.7 monocytic murine cell line. PKA, Epac1/2 (signaling intermediates for cAMP) and A2AR knockdowns were performed by shRNA transfection and interactions with A2AR and A2BR, as well as with methotrexate were tested in vitro and in the murine air pouch model. Statistical differences were determined using one or two-way ANOVA or Student's t test. The alpha nominal level was set at 0.05 in all cases. A P value of < 0.05 was considered significant.
resultsIn vitro, apremilast increased intracellular cAMP and inhibited TNF-α release (IC50=104nM) and the specific A2AR-agonist CGS21680 (1μM) increased apremilast potency (IC50=25nM). In this cell line, apremilast increased IL-10 production. PKA, Epac1 and Epac2 knockdowns prevented TNF-α inhibition and IL-10 stimulation by apremilast. In the murine air pouch model, both apremilast and MTX significantly inhibited leukocyte infiltration, while apremilast, but not MTX, significantly inhibited TNF-α release. The addition of MTX (1 mg/kg) to apremilast (5 mg/kg) yielded no more inhibition of leukocyte infiltration or TNF-α release than with apremilast alone.
conclusionsThe immunoregulatory effects of apremilast appear to be mediated by cAMP through the downstream effectors PKA, Epac1, and Epac2. A2AR agonism potentiated TNF-α inhibition by apremilast, consistent with the cAMP-elevating effects of that receptor. Because the A2AR is also involved in the anti-inflammatory effects of MTX, the mechanism of action of both drugs involves cAMP-dependent pathways and is therefore partially overlapping in nature.
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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.