title: Phosphodiesterase 4 in inflammatory diseases: Effects of apremilast in psoriatic blood and in dermal myofibroblasts through the PDE4/CD271 complex.
abstract: Phosphodiesterases 4 (PDE4) act as proinflammatory enzymes via degradation of cAMP, whereas PDE4 inhibitors play an anti-inflammatory role in vitro and in vivo. In particular, apremilast has been recently approved for the treatment of psoriasis and psoriatic arthritis. However, little is known on the expression pattern of PDE4 in psoriasis. We report that PDE4B and PDE4D mRNA are overexpressed in peripheral blood mononuclear cells (PBMC) from psoriasis, as compared with normal controls, while apremilast reduces PBMC production of a number of pro-inflammatory cytokines and increases the levels of anti-inflammatory mediators. PDE4 expression is up-regulated in psoriatic dermis as compared with normal skin, with particular regard to fibroblasts. This is confirmed in vitro, where both dermal fibroblasts (DF) and, to a greater extent, myofibroblasts (DM) express all PDE4 isoforms at the mRNA and protein level. Because PDE4 interacts with the nerve growth factor (NGF) receptor CD271 in lung fibroblasts, we evaluated the relationship and function of PDE4 and CD271 in normal human skin fibroblasts. All PDE4 isoforms co-immunoprecipitate with CD271 in DM, while apremilast inhibits apoptosis induced by β-amyloid, a CD271 ligand, in DM. Furthermore, apremilast significantly reduces NGF- and transforming growth factor-β1 (TGF-β1)-induced fibroblast migration, and inhibits DF differentiation into DM mediated by NGF or TGF-β1. Finally, in DM, apremilast significantly reduces cAMP degradation induced by treatment with β-amyloid. Taken together, these results indicate that PDE4 play an important role in psoriasis. In addition, the study reveals that the PDE4/CD271 complex could be important in modulating fibroblast functions.
authors.affiliation: Sol J. Barer Laboratories, Celgene Corporation, Summit, NJ, USA. Electronic address: pschafer@celgene.com.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Schafer
authors.affiliation: Laboratory of Cutaneous Biology, Department of Surgical, Medical, Dental and Morphological Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Truzzi
authors.affiliation: Sol J. Barer Laboratories, Celgene Corporation, Summit, NJ, USA.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Parton
authors.affiliation: Sol J. Barer Laboratories, Celgene Corporation, Summit, NJ, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Wu
authors.affiliation: Sol J. Barer Laboratories, Celgene Corporation, Summit, NJ, USA.
authors.forename: Jolanta
authors.initials: J
authors.lastname: Kosek
authors.affiliation: Sol J. Barer Laboratories, Celgene Corporation, Summit, NJ, USA.
authors.forename: Ling-Hua
authors.initials: LH
authors.lastname: Zhang
authors.affiliation: Sol J. Barer Laboratories, Celgene Corporation, Summit, NJ, USA.
authors.forename: Gerald
authors.initials: G
authors.lastname: Horan
authors.affiliation: Laboratory of Cutaneous Biology, Department of Surgical, Medical, Dental and Morphological Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Saltari
authors.affiliation: Laboratory of Cutaneous Biology, Department of Surgical, Medical, Dental and Morphological Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Marika
authors.initials: M
authors.lastname: Quadri
authors.affiliation: Laboratory of Cutaneous Biology, Department of Surgical, Medical, Dental and Morphological Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Lotti
authors.affiliation: Laboratory of Cutaneous Biology, Department of Surgical, Medical, Dental and Morphological Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Marconi
authors.affiliation: Laboratory of Cutaneous Biology, Department of Surgical, Medical, Dental and Morphological Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Pincelli
mesh_terms: D000068816:Adapalene / Q000378:metabolism*; D000328:Adult; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D020405:Dermis / Q000473:pathology*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D007249:Inflammation / Q000097:blood / Q000201:enzymology* / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D058628:Myofibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D011565:Psoriasis / Q000097:blood* / Q000201:enzymology* / Q000473:pathology; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D007527:Isoenzymes; D000068816:Adapalene; D013792:Thalidomide; D000242:Cyclic AMP; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C505730:apremilast
keywords: Apremilast; CD271; Myofibroblasts; PBMC; PDE4; Psoriasis