Mechanisms of antipsoriatic effects of phosphodiesterase 4 inhibitors

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Author:
HUANG Ying-xue(Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing 210042, China)
LI Xin-yu(Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing 210042, China)
Journal Title:
INTERNATIONAL JOURNAL OF DERMATOLOGY AND VENEREOLOGY
Issue:
Volume 37, Issue 03, 2011
DOI:
10.3760/cma.j.issn.1673-4173.2011.03.006
Key Word:
Psoriasis;Cytokines;Phosphodiesterase 4

Abstract: The phosphodiesterase (PDE) 4 is a predominant cyclic adenosine monophosphate (cAMP)degrading enzyme which can mediate inflammatory reactions via several routes. With broad anti-inflammatory activities, PDE4 inhibitors perform an antipsoriatic effect via a multifaceted and multitarget mechanism. Concretely, they can downregulate the production of pre-inflammatory cytokines including tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-12 and IL-23 by modulating gene expression, inhibit the activation of dendrite cells and T cells and reduce the synthesis of inflammatory mediators. In addition, they have an anti-angiogenic potential. The efficacy and safety of PDE4 inhibitors have been confirmed in clinical trails. Thus, selective PDE4 inhibitors have excellent potential as new options for the treatment of psoriasis.

  • [1]Dastidar SG,Rajagopal D,Ray A.Therapeutic benefit of PDE4 inhibitors in inflammatory diseases.Curt Opin lnvestig Drugs,2007,8(5):364-372.
  • [2]Keravis T,Lugnier C.Cyclic nucleotide phosphodiesterases (PDE) and peptide motifs.Curr Pharm Des,2010,16(9):1114-1125.
  • [3]Higgs G.Is PDE4 too difficult a drug target? Curr Opin Investig Drugs,2010,11 (5):495-498.
  • [4]Man HW,Schafer P,Wong LM,et al.Discovery of (S)-N-[2-[1-(3-ethoxy-4-methoxyphenyl) -2-methanesulfonylethyl]-1,3-dioxo 2,3-dihydro-1H-isoindol-4-yl] acetamide (apremilast).a potent and orally active phosphodiesterase 4 and tumor necrosis factor alpha inhibitor.J Med Chem,2009,52(6):1522-1524.
  • [5]Schett G,Sloan VS,Stevens RM,et al.Apremilast:a novel PDE4 inhibitor in the treatment of autoimmune and inflammatory diseases.Ther Adv Musculoskelet Dis,2010,2(5):271-278.
  • [6]Harada D,Tsukumo Y,Takashima Y,et al.Effect of orally administered rolipram,a phosphodiesterase 4 inhibitor,on a mouse model of the dermatitis caused by 2,4,6-trinitro-1-chlorobenzene (TNCB)-repeated application.Eur J Pharmacol,2006,532(1-2):128-137.
  • [7]B(a)umer W,Hoppmann J,Rundfeldt C,et al.Highly selective phosphodiesterase 4 inhibitors for the treatment of allergic skin diseases and psoriasis.Inflamm Allergy Drug Targets,2007,6 (1):17-26.
  • [8]Harada D,Takada C,Nosaka Y,et al.Effect of orally administered KF66490,a phosphodiesterase 4 inhibitor,on dermatitis in mouse models.Int Immunopharmacol,2009,9(1):55-62.
  • [9]Nazarian R,Weinberg JM.AN-2728,a PDE4 inhibitor for the potential topical treatment of psoriasis and atopic dermatitis.Curr Opin Investig Drugs,2009,10(11):1236-1242.
  • [10]Schafer PH,Parton A,Gandhi AK,et al.Apremilast,a cAMP phosphodiesterase-4 inhibitor,demonstrates anti-inflammatory activity in vitro and in a model of psoriasis.Br J Pharmacol,2010,159(4):842-855.
  • [11]Gottlieb AB,Strober B,Krueger JG,et al.An open-label,single arm pilot study in patients with severe plaque-type psoriasis treated with an oral anti-inflammatory agent,apremilast.Curr Med Res Opin,2008,24(5):1529-1538.
  • [12]Nestle FO,Kaplan DH,Barker J.Psoriasis.N Engl J Med,2009,361(5):496-509.
  • [13]Blauvelt A.T-helper 17 cells in psoriatic plaques and additional genetic links between IL-23 and psoriasis.J Invest Dermatol,2008,128(5):1064-1067.
  • [14]Zaba LC,Cardinale I,Gilleaudeau P,et al.Amelioration of epidermal hyperplasia by TNF inhibition is associated with reduced Th17 responses.J Exp Med,2007,204(13):3183-3194.
  • [15]Asadullah K,Sabat R,Friedrich M,et al.Interleukin-10:an important immunoregulatory cytokine with major impact on psoriasis.Curr Drug Targets Inflamm Allergy,2004,3(2):185-192.
  • [16]Bos JD,de Rie MA,Teunissen MB,et al.Psoriasis:dysregulation of innate immunity.Br J Dermatol,2005,152(6):1098-1107.
  • [17]Lowes MA,Bowcock AM,Krueger JG.Pathogenesis and therapy of psoriasis.Nature,2007,445(7130):866-873.
  • [18]Conrad C,Boyman O,Tonel G,et al.Alphalbetal integrin is crucial for accumulation of epidermal T cells and the development of psoriasis.Nat Med,2007,13(7):836-842.
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