Phosphodiesterase 4 in inflammatory diseases: Effects of apremilast in psoriatic blood and in dermal myofibroblasts through the PDE4/CD271 complex
| Autor: | Annalisa Saltari, M. Quadri, Ling-Hua Zhang, Alessandra Marconi, Anastasia Parton, Carlo Pincelli, Peter H. Schafer, Roberta Lotti, Gerald Horan, Lei Wu, Jolanta Kosek, Francesca Truzzi |
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| Jazyk: | angličtina |
| Předmět: |
0301 basic medicine
Adult Male Apremilast CD271 Myofibroblasts PBMC PDE4 Psoriasis Cell Biology Gene Expression Regulation Enzymologic Fibroblast migration Proinflammatory cytokine 03 medical and health sciences Psoriatic arthritis 0302 clinical medicine PDE4B Cell Movement medicine Cyclic AMP Humans Immunoprecipitation Adapalene Fibroblast Inflammation Chemistry Phosphodiesterase Cell Differentiation Dermis medicine.disease Immunohistochemistry Cyclic Nucleotide Phosphodiesterases Type 4 Thalidomide Isoenzymes 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Immunology Cancer research Leukocytes Mononuclear Cytokines Female Inflammation Mediators medicine.drug |
| Zdroj: | Cellular Signalling. (7):753-763 |
| ISSN: | 0898-6568 |
| DOI: | 10.1016/j.cellsig.2016.01.007 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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