Look inside the cell for a new perspective
Discover the Role of PDE4 in Autoimmune Disease
Phosphodiesterase 4 (PDE4) promotes the dysregulation of pro- and anti-inflammatory mediators released by various cell types and has been implicated in several inflammatory diseases, including psoriasis, psoriatic arthritis, ankylosing spondylitis, and other autoimmune diseases.
Intracellular Pro- and
The immune system is finely balanced by the activities of pro- and anti-inflammatory mediators.
PDE4 is a Key Enzyme Involved in Regulating 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 a network of proinflammatory mediators , including tumor necrosis factor (TNF)-α,3 interleukin (IL)-17,4 IL-224 and interferon (IFN)-γ.5 It is also believed that cAMP promotes the production of anti-inflammatory mediators such as IL-10.6
Psoriatic disease is associated with aberrant inflammation and the production of a network 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 psoriatic diseases resulting from proinflammatory signaling will be explored.
- 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 Joshi R. Immunopathogenesis of psoriasis. Indian J Dermatol Venereol Leprol. 2004;70:10‑12.
- 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.
- 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 Wollina U, Unger L, Heinig B, Kittner T. Psoriatic arthritis. Dermatol Ther. 2010;23:123‑136.