Discover the Role of PDE4 in Psoriasis and Psoriatic Arthritis

Phosphodiesterase 4 (PDE4) promotes the dysregulation of pro- and anti-inflammatory mediators released by various cell types and has been implicated in psoriasis, psoriatic arthritis, and other autoimmune diseases.

PDE4 and Psoriasis

PDE4 and
Psoriasis

PDE4 plays an important role in the chronic inflammation associated with the development of skin symptoms in psoriasis.85

PDE4 and Psoriatic Arthritis

PDE4 and
Psoriatic Arthritis

PDE4 plays an important role in the chronic inflammation of the joints and skin symptoms associated with psoriatic arthritis.85

PDE4 Is a Key Enzyme Involved in Modulating Production
of Inflammatory Mediators by Immune Cells

Phosphodiesterase 4 (PDE4) is the predominant enzyme that degrades the second messenger cAMP in many immune cells, including eosinophils, neutrophils, macrophages, T cells, and monocytes.1 Proinflammatory mediators released by those cells lead to activation of and tissue infiltration by other immune cells, as well as activation and hyperproliferation of keratinocytes; this process could play a role in the development of psoriatic lesions.2 Evidence suggests that cAMP causes a downregulatory signal in immune cells, thus suppressing the production of proinflammatory mediators, including tumor necrosis factor (TNF)-α,3 interleukin (IL)-17,4 and interferon (IFN)-γ.5 It is also believed that cAMP promotes the production of anti-inflammatory mediators such as IL-10.6

Psoriasis and psoriatic arthritis are associated with aberrant inflammation and the production of proinflammatory mediators.2 Psoriasis and psoriatic arthritis are inflammatory diseases with overlapping features and shared immunologic mechanisms.2 Psoriasis is a systemic disease in that it primarily affects the skin but up to 40% of individuals with psoriasis may go on to develop psoriatic arthritis.7 Psoriatic arthritis typically affects the peripheral joints and can occasionally affect the spine and sacroiliac area.8 Enthesitis, dactylitis, and nail changes such as pitting and discoloration are also common manifestations of psoriatic disease in patients with joint involvement.8 The chronic nature of psoriasis and psoriatic arthritis resulting from proinflammatory signaling will be explored.

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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.

Enthesitis

Inflammation at the site of muscle insertion.

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.

Inflammatory

Pertaining to, characterized by, causing, resulting from, or becoming affected by inflammation.

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 (PDE)

Enzymes that cleave bonds in phosphodiesters, such as those in cAMP.

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.

Psoriasis

A common dermatologic condition characterized by the eruption of circumscribed, discrete and confluent, reddish, silvery‑scaled maculopapules; the lesions occur predominantly on the elbows, knees, scalp, and trunk, and microscopically show characteristic parakeratosis and elongation of rete ridges with shortening of epidermal keratinocyte transit time due to decreased cyclic guanosine monophosphate

Psoriatic Arthritis

A form of polyarthritis (ie, affecting more than one joint) that occurs in patients with psoriasis; the arthritis resembles rheumatoid arthritis but is seronegative for rheumatoid factor and often involves the digits.

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. 2 Joshi R. Immunopathogenesis of psoriasis. Indian J Dermatol Venereol Leprol. 2004;70:10‑12.
  3. 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. 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. 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. 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.
  7. 7 Winterfield LS, Menter A, Gordon K, Gottlieb A. Psoriasis treatment: current and emerging directed therapies. Ann Rheum Dis. 2005;64 Suppl 2:ii87‑ii90.
  8. 8 Wollina U, Unger L, Heinig B, Kittner T. Psoriatic arthritis. Dermatol Ther. 2010;23:123‑136.
  9. 85 Schett G, Elewaut D, McInnes IB, Dayer JM, Neurath MF. How cytokine networks fuel inflammation: Toward a cytokine-based disease taxonomy. Nat Med. Jul 2013;19(7):822-824.