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
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Glossary:

Cyclic adenosine monophosphate (cAMP)

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.

Adenosine monophosphate (AMP), or adenylic acid

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.

Inflammation (or inflammatory response)

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.

Interferons (IFN)

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.

Interleukin (IL)

Any of a group of multifunctional cytokines synthesized by lymphocytes, monocytes, macrophages, and lymphoid and nonlymphoid cells.

Phosphodiesterase 4 (PDE4)

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.

Tumor necrosis factor (TNF)

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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References:

  1. 1 Bäumer W, Hoppmann J, Rundfeldt C, Kietzmann M. Highly selective phosphodiesterase 4 inhibitors for the treatment of allergic skin diseases and psoriasis. Inflamm Allergy Drug Targets. 2007;6:17‑26.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. 32 Mehats C, Jin SL, Wahlstrom J, Law E, Umetsu DT, Conti M. PDE4D plays a critical role in the control of airway smooth muscle contraction. FASEB J. 2003;17:1831‑1841.
  7. 34 Chujor CS, Hammerschmid F, Lam C. Cyclic nucleotide phosphodiesterase 4 subtypes are differentially expressed by primary keratinocytes and human epidermoid cell lines. J Invest Dermatol. 1998;110:287‑291.
  8. 35 Tenor H, Hedbom E, Hauselmann HJ, Schudt C, Hatzelmann A. Phosphodiesterase isoenzyme families in human osteoarthritis chondrocytes‑‑functional importance of phosphodiesterase 4. Br J Pharmacol. 2002;135:609‑618.
  9. 36 Carlson CR, Lygren B, Berge T, et al. Delineation of type I protein kinase A‑selective signaling events using an RI anchoring disruptor. J Biol Chem. 2006;281:21535‑21545.
  10. 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.
  11. 38 Essayan DM, Huang SK, Kagey‑Sobotka A, Lichtenstein LM. Differential efficacy of lymphocyte‑ and monocyte‑selective pretreatment with a type 4 phosphodiesterase inhibitor on antigen‑driven proliferation and cytokine gene expression. J Allergy Clin Immunol. 1997;99:28‑37.
  12. 39 Layseca‑Espinoza E, Sánchez‑Madrid F, González‑Amaro R. Phosphodiesterase inhibitors as immunomodulatory drugs. Immunología. 2003;22:39‑52.