Abstract
Phosphodiesterase (PDE) 4 is a superfamily of enzymes that catalyze the hydrolysis of cyclic adenosine 3',5'-monophosphate (cAMP), an intracellular second messenger and regulator of a wide array of genes and proteins. Increased levels of intracellular cAMP lead to activation of genes but also to inhibition of nuclear factor-kappa B, involved in pro-inflammatory responses. By increasing cAMP levels, PDE4 inhibitors, such as apremilast, reduced production of pro-inflammatory TNFα, IFNγ, and IL-17 and increased production of anti-inflammatory IL-10 in lipopolysaccharide-stimulated peripheral blood mononuclear cells, and in patients with psoriatic arthritis (PsA). Among PDE4 inhibitors, apremilast, roflumilast, and crisabolore have been approved for the treatment of psoriasis and PsA, chronic obstructive pulmonary disease, and atopic dermatitis, respectively. In a preliminary study on psoriasis and PsA we showed that at 6 months apremilast decreased IFNγ+CD3+ Th1 cells and IL- 17+CD3+ Th17 cells and increased regulatory B cells and regulatory T cells. In this review, we highlight recent findings of PDE4 inhibitors in atopic dermatitis, alopecia areata, uveitis, rheumatoid arthritis, psoriasis and PsA, systemic lupus erythematosus, vasculitis, systemic sclerosis, multiple sclerosis and inflammatory bowel disease. Given the role of cAMP as second messenger in diverse intracellular pathways, selective PDE4 inhibitors are likely to be therapeutic agents for various immune mediated diseases.
Keywords: Apremilast, autoimmunity, bregs, cAMP, tregs, psoriatic arthritis, psoriasis.
Current Medicinal Chemistry
Title:Phosphodiesterase 4 Inhibitors in Immune-mediated Diseases: Mode of Action, Clinical Applications, Current and Future Perspectives
Volume: 24 Issue: 28
Author(s): Lazaros I. Sakkas*, Athanasios Mavropoulos and Dimitrios P. Bogdanos
Affiliation:
- Department of Rheumatology and clinical Immunology Faculty of Medicine, School of Health Science University of Thessaly, Larissa 41 110,Greece
Keywords: Apremilast, autoimmunity, bregs, cAMP, tregs, psoriatic arthritis, psoriasis.
Abstract: Phosphodiesterase (PDE) 4 is a superfamily of enzymes that catalyze the hydrolysis of cyclic adenosine 3',5'-monophosphate (cAMP), an intracellular second messenger and regulator of a wide array of genes and proteins. Increased levels of intracellular cAMP lead to activation of genes but also to inhibition of nuclear factor-kappa B, involved in pro-inflammatory responses. By increasing cAMP levels, PDE4 inhibitors, such as apremilast, reduced production of pro-inflammatory TNFα, IFNγ, and IL-17 and increased production of anti-inflammatory IL-10 in lipopolysaccharide-stimulated peripheral blood mononuclear cells, and in patients with psoriatic arthritis (PsA). Among PDE4 inhibitors, apremilast, roflumilast, and crisabolore have been approved for the treatment of psoriasis and PsA, chronic obstructive pulmonary disease, and atopic dermatitis, respectively. In a preliminary study on psoriasis and PsA we showed that at 6 months apremilast decreased IFNγ+CD3+ Th1 cells and IL- 17+CD3+ Th17 cells and increased regulatory B cells and regulatory T cells. In this review, we highlight recent findings of PDE4 inhibitors in atopic dermatitis, alopecia areata, uveitis, rheumatoid arthritis, psoriasis and PsA, systemic lupus erythematosus, vasculitis, systemic sclerosis, multiple sclerosis and inflammatory bowel disease. Given the role of cAMP as second messenger in diverse intracellular pathways, selective PDE4 inhibitors are likely to be therapeutic agents for various immune mediated diseases.
Export Options
About this article
Cite this article as:
Sakkas I. Lazaros*, Mavropoulos Athanasios and Bogdanos P. Dimitrios , Phosphodiesterase 4 Inhibitors in Immune-mediated Diseases: Mode of Action, Clinical Applications, Current and Future Perspectives, Current Medicinal Chemistry 2017; 24 (28) . https://dx.doi.org/10.2174/0929867324666170530093902
DOI https://dx.doi.org/10.2174/0929867324666170530093902 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Approaches to the treatment of chronic inflammation
Chronic inflammation is a hallmark of numerous diseases, significantly impacting global health. Although chronic inflammation is a hot topic, not much has been written about approaches to its treatment. This thematic issue aims to showcase the latest advancements in chronic inflammation treatment and foster discussion on future directions in this ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Nontuberculous Mycobacterium Infections in Rheumatoid Arthritis Patients: The Serodiagnosis of Pulmonary Disease due to Mycobacterium avium Complex with an Enzyme Immunoassay Kit Detecting Glycopeptidolipid Core Antigen (Capilia MAC Antibody ELISA)<sup>®</sup>)
Current Rheumatology Reviews The Use of Interferons in Respiratory Diseases
Current Respiratory Medicine Reviews Desensitization for Drug Hypersensitivity to Chemotherapy and Monoclonal Antibodies
Current Pharmaceutical Design Recent Clinical Evidence for the Treatment of Osteoarthritis: What we have Learned
Reviews on Recent Clinical Trials Protective Role of Diabetes Mellitus on Abdominal Aortic Aneurysm Pathogenesis: Myth or Reality?
Current Vascular Pharmacology Applications of FDG-PET/CT in Assessment of Vascular Infection and Inflammation
Current Molecular Imaging (Discontinued) Editorial (Thematic Issue: Biologics in Autoimmune Diseases)
Current Pharmaceutical Biotechnology Mechanisms of Corticosteroid Resistance in Severe Asthma and Chronic Obstructive Pulmonary Disease (COPD)
Current Pharmaceutical Design Aldose Reductase Enzyme and its Implication to Major Health Problems of the 21st Century
Current Medicinal Chemistry Cefpodoxime Proxetil-Related Hemolysis and Acute Interstitial Nephritis
Current Drug Safety A Very Rare Cerebral Complication of Chemotherapy in a Young Girl: A Difficult Diagnosis
Current Drug Safety Fibroblast Growth Factor 2: From Laboratory Evidence to Clinical Application
Current Vascular Pharmacology Intravenous Immunoglobulin as a Potential Therapy for Refractory Urticaria - A Review
Inflammation & Allergy - Drug Targets (Discontinued) Alterations in the Vascular Reactivity of Aorta in the Early and Late Phase of Adjuvant-Induced Arthritis in Rat
Vascular Disease Prevention (Discontinued) Amyloid A Amyloidosis Secondary to Rheumatoid Arthritis: An Uncommon Yet Important Complication
Current Rheumatology Reviews Retracted: Tocotrienols and its Role in Cardiovascular Health- a Lead for Drug Design
Current Pharmaceutical Design The Pathology Induced by Highly Active Antiretroviral Therapy Against Human Immunodeficiency Virus: an Update
Current Medicinal Chemistry A UPLC-MS/MS Method for Simultaneous Determination of Six Bioactive Compounds in Rat Plasma, and its Application to Pharmacokinetic Studies of Naoshuantong Granule in Rats
Current Pharmaceutical Analysis Diabetes and Its Complications: Therapies Available, Anticipated and Aspired
Current Diabetes Reviews Mechanisms of Neutrophil-mediated Disease: Innovative Therapeutic Interventions
Current Pharmaceutical Design