Role of PDE4 in Psoriatic Arthritis

Psoriatic arthritis (PsA) is associated with aberrant inflammation and the production of proinflammatory mediators that potentiate psoriatic arthritis. Proinflammatory mediators are released by a variety of cell types, including innate and adaptive immune cells and resident nonimmune cells. The inappropriate release of proinflammatory mediators could explain the chronic inflammation and subsequent changes in the resident cells of the skin and joints in cases of psoriatic arthritis.

Current pre-clinical research regarding the immunopathogenesis of psoriatic arthritis supports the hypothesis that a dysregulated immune system is governed by proinflammatory cytokines, including TNF-α, IL-17, and other cytokines contributing to the development of psoriatic arthritis.46, 96 These findings provide clinical evidence that increased levels of proinflammatory mediators are found in the lesions and synovium of patients with psoriatic arthritis.41, 43, 44, 45, 46

PDE4 is present in inflammatory cells that are relevant in psoriatic arthritis and is involved in several pathophysiological processes. PDE4 is the predominant cAMP-degrading enzyme in a variety of inflammatory cells, including eosinophils, neutrophils, macrophages, T cells, and monocytes.1 PDE4 plays an important role in the regulation of the pro- and anti-inflammatory mediators that are involved in psoriatic arthritis. Dysregulation of the production of pro- and anti-inflammatory mediators in joint-resident cells in the synovium could account for the characteristic swelling and tenderness of psoriatic arthritis.44

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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.

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.

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. 41 van Kuijk AW, Reinders‑Blankert P, Smeets TJ, Dijkmans BA, Tak PP. Detailed analysis of the cell infiltrate and the expression of mediators of synovial inflammation and joint destruction in the synovium of patients with psoriatic arthritis: implications for treatment. Ann Rheum Dis. 2006;65:1551‑1557.
  3. 43 Spadaro A, Rinaldi T, Riccieri V, Valesini G, Taccari E. Interleukin 13 in synovial fluid and serum of patients with psoriatic arthritis. Ann Rheum Dis. 2002;61:174‑176.
  4. 44 Ritchlin C, Haas‑Smith SA, Hicks D, Cappuccio J, Osterland CK, Looney RJ. Patterns of cytokine production in psoriatic synovium. J Rheumatol. 1998;25:1544‑1552.
  5. 45 Fiocco U, Sfriso P, Oliviero F, et al. Synovial effusion and synovial fluid biomarkers in psoriatic arthritis to assess intraarticular tumor necrosis factor‑alpha blockade in the knee joint. Arthritis Res Ther. 2010;12:R148.
  6. 46 Raychaudhuri SP, Raychaudhuri SK, Genovese MC. IL‑17 receptor and its functional significance in psoriatic arthritis. Mol Cell Biochem. 2012;359:419‑429.
  7. 96 Veale DJ, Ritchlin C, FitzGerald O. Immunopathology of psoriasis and psoriatic arthritis. Ann Rheum Dis. 2005;64 Suppl 2:ii26-29.