PDE4 and Proinflammatory Mediators
In a 2007 review, Bäumer and colleagues concluded that PDE4 is the predominant cyclic AMP-degrading enzyme in a variety of inflammatory cells, including eosinophils, neutrophils, macrophages, T cells, and monocytes.1
PDE4 plays an important role in promoting the inflammatory response. PDE4 exerts its proinflammatory effect by degrading cAMP in inflammatory cells, smooth muscle cells, endothelial cells, and keratinocytes. PDE4 increases the production of TNF-α, IL-17, and IFN-γ, which are all proinflammatory mediators.11, 12, 13 At the same time, PDE4 decreases the production of anti-inflammatory mediators such as IL-10.6 The role of PDE4 in promoting the inflammatory response can help to explain PDE4's role in balancing contraction and relaxation of the smooth muscle in airways.32
- IL-12 production in macrophages, which is important for the differentiation of T-helper 1 cells, is also regulated by PDE4.12
- Mesenchymal cells that express PDE4 include keratinocytes within the dermis34 and chondrocytes involved in the structure of the joint.35
- In T cells, cAMP is involved in a pathway that suppresses the activation of the T cell.36, 37 By breaking down cAMP in T cells, PDE4 promotes the production of TNF-α, IL-2, IL-4, and IL-5 and the proliferation of T cells.38, 39
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.
A condensation product of adenosine and phosphoric acid; a nucleotide found among the hydrolysis products of all nucleic acids. 3'‑Adenylic acid (adenosine 3'‑monophosphate) and 5'‑adenylic acid [adenosine 5'‑monophosphate (AMP)] differ in the place of attachment of the phosphoric acid to the D‑ribose; deoxyadenylic acid differs in having H instead of OH at the 2' position of D‑ribose.
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.
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.
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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- 37 Phosphodiesterases As Drug Targets. Francis SH, Houslay MD, Conti M, eds. Phosphodiesterases As Drug Targets. Berlin‑Heidelberg, Germany: Springer‑Verlag, 2011. Handbook of Experimental Pharmacology.
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