PDE4 Plays a Major Role in Regulating Immune Cells'
Production of Mediators of Inflammation
PDE4 is an intracellular enzyme that promotes production of proinflammatory mediators and decreases production of anti-inflammatory mediators. Phosphodiesterase 4 (PDE4) promotes inflammation by degrading intracellular levels of cyclic adenosine monophosphate (cAMP), a naturally occurring second messenger that helps maintain immune homeostasis. PDE4 degradation of cAMP can cause immune cell activation and the release of proinflammatory mediators such as TNF-α, IL-17, and IFN-γ.11, 12, 13 By breaking down cAMP, PDE4 indirectly decreases the production of anti-inflammatory mediators such as IL-10.6 PDE4 has been implicated in a number of inflammatory diseases, including psoriasis, psoriatic arthritis, and ankylosing spondylitis.
PDE4 Is the Predominant Phosphodiesterase
Active in Immune Cells
PDE4 is the predominant cAMP-degrading enzyme in a variety of inflammatory cells, including eosinophils, neutrophils, macrophages, T cells, and monocytes.1 PDE4 is an intracellular enzyme that promotes production of proinflammatory mediators and decreases production of anti-inflammatory mediators.3, 4, 5, 6
PDE4 Potentiates the Proinflammatory Response and Is Present Within Key Psoriatic Inflammatory Cells
Once activated, immune cells release proinflammatory mediators that can activate other cells and promote proliferation, recruiting more cells to the site of disease.31 In psoriatic disease, this process does not resolve; thus, it disrupts immune homeostasis and results in a chronic cycle of inflammation.
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See PDE4’s Role in Autoimmune Disease
An activator of phosphorylase kinase and an effector of other enzymes, formed in muscle from ATP by adenylate cyclase and broken down to 5'‑AMP by a phosphodiesterase; the first known second messenger, it is a regulator of metabolism. A related compound (2',3') is also known.
The general term for histologically apparent cytologic changes, cellular infiltration, and mediator release that occurs in affected blood vessels and adjacent tissue in response to injury or abnormal stimulation. The so‑called cardinal signs of rubor (redness), calor (heat), tumor (swelling), and dolor (pain) may or may not be present.
Pertaining to, characterized by, causing, resulting from, or becoming affected by inflammation.
Cytokines produced by T cells, fibroblasts, and other cells in response to viral infection and other biologic and synthetic stimuli; IFNs bind to specific receptors on cell membranes.
Any of a group of multifunctional cytokines synthesized by lymphocytes, monocytes, macrophages, and lymphoid and nonlymphoid cells.
Enzymes that cleave bonds in phosphodiesters, such as those in cAMP.
A key enzyme involved in the cytokine production of inflammatory cells. PDE4 is an intracellular enzyme that promotes inflammation by degrading intracellular levels of cyclic adenosine monophosphate (cAMP), a naturally occurring second messenger that helps maintain immune homeostasis by modulating the production of pro‑ and anti‑inflammatory mediators.
Any of several cytokines that function as cell‑associated or secreted proteins interacting with receptors of the tumor necrosis factor receptor (TNFR) family.
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- 3 Souness JE, Griffin M, Maslen C, et al. Evidence that cyclic AMP phosphodiesterase inhibitors suppress TNF alpha generation from human monocytes by interacting with a 'low‑affinity' phosphodiesterase 4 conformer. Br J Pharmacol. 1996;118:649‑658.
- 4 Ma R, Yang BY, Wu CY. A selective phosphodiesterase 4 (PDE4) inhibitor Zl‑n‑91 suppresses IL‑17 production by human memory Th17 cells. Int Immunopharmacol. 2008;8:1408‑1417.
- 5 Essayan DM, Huang SK, Kagey‑Sobotka A, Lichtenstein LM. Effects of nonselective and isozyme selective cyclic nucleotide phosphodiesterase inhibitors on antigen‑induced cytokine gene expression in peripheral blood mononuclear cells. Am J Respir Cell Mol Biol. 1995;13:692‑702.
- 6 Oger S, Mehats C, Dallot E, Cabrol D, Leroy MJ. Evidence for a role of phosphodiesterase 4 in lipopolysaccharide‑stimulated prostaglandin E2 production and matrix metalloproteinase‑9 activity in human amniochorionic membranes. J Immunol. 2005;174:8082‑8089.
- 11 Jimenez JL, Punzon C, Navarro J, Munoz‑Fernandez MA, Fresno M. Phosphodiesterase 4 inhibitors prevent cytokine secretion by T lymphocytes by inhibiting nuclear factor‑kappaB and nuclear factor of activated T cells activation. J Pharmacol Exp Ther. 2001;299:753‑759.
- 12 Liu J, Chen M, Wang X. Calcitonin gene‑related peptide inhibits lipopolysaccharide‑induced interleukin‑12 release from mouse peritoneal macrophages, mediated by the cAMP pathway. Immunology. 2000;101:61‑67.
- 13 Sheibanie AF, Tadmori I, Jing H, Vassiliou E, Ganea D. Prostaglandin E2 induces IL‑23 production in bone marrow‑derived dendritic cells. FASEB J. 2004;18:1318‑1320.
- 31 Johnson‑Huang LM, McNutt NS, Krueger JG, Lowes MA. Cytokine‑producing dendritic cells in the pathogenesis of inflammatory skin diseases. J Clin Immunol. 2009;29:247‑256.