PDE4 inhibition by difamilast regulates filaggrin and loricrin expression via keratinocyte proline-rich protein in human keratinocytes.
Atopic dermatitis
Filaggrin
KPRP
Loricrin
PDE4
Journal
Journal of dermatological science
ISSN: 1873-569X
Titre abrégé: J Dermatol Sci
Pays: Netherlands
ID NLM: 9011485
Informations de publication
Date de publication:
May 2023
May 2023
Historique:
received:
14
10
2022
revised:
06
04
2023
accepted:
26
04
2023
medline:
5
6
2023
pubmed:
9
5
2023
entrez:
8
5
2023
Statut:
ppublish
Résumé
Difamilast, a topical phosphodiesterase 4 (PDE4) inhibitor, has been shown to be effective for treating atopic dermatitis (AD), but the molecular mechanism involved is unclear. Since skin barrier dysfunction including reduced expression of filaggrin (FLG) and loricrin (LOR) contributes to AD development, difamilast treatment may be able to improve this dysfunction. PDE4 inhibition increases transcriptional activity of cAMP-responsive element binding protein (CREB). Therefore, we hypothesized that difamilast may affect FLG and LOR expression via CREB in human keratinocytes. To elucidate the mechanism by which difamilast regulates FLG and LOR expression via CREB in human keratinocytes. We analyzed normal human epidermal keratinocytes (NHEKs) treated with difamilast. We observed increases of intracellular cAMP levels and CREB phosphorylation in difamilast (5 μM)-treated NHEKs. Next, we found that difamilast treatment increased mRNA and protein levels of FLG and LOR in NHEKs. Since reduced expression of keratinocyte proline-rich protein (KPRP) is reported to be involved in skin barrier dysfunction in AD, we examined KPRP expression in difamilast-treated NHEKs. We found that difamilast treatment increased mRNA and protein levels of KPRP in NHEKs. Furthermore, KPRP knockdown using siRNA transfection abolished the upregulation of FLG and LOR in difamilast-treated NHEKs. Finally, CREB knockdown canceled the upregulation of FLG, LOR, and KPRP in difamilast-treated NHEKs, indicating that PDE4 inhibition by difamilast treatment positively regulates FLG and LOR expression via the CREB-KPRP axis in NHEKs. These findings may provide further guidance for therapeutic strategies in the treatment of AD using difamilast.
Sections du résumé
BACKGROUND
BACKGROUND
Difamilast, a topical phosphodiesterase 4 (PDE4) inhibitor, has been shown to be effective for treating atopic dermatitis (AD), but the molecular mechanism involved is unclear. Since skin barrier dysfunction including reduced expression of filaggrin (FLG) and loricrin (LOR) contributes to AD development, difamilast treatment may be able to improve this dysfunction. PDE4 inhibition increases transcriptional activity of cAMP-responsive element binding protein (CREB). Therefore, we hypothesized that difamilast may affect FLG and LOR expression via CREB in human keratinocytes.
OBJECTIVE
OBJECTIVE
To elucidate the mechanism by which difamilast regulates FLG and LOR expression via CREB in human keratinocytes.
METHODS
METHODS
We analyzed normal human epidermal keratinocytes (NHEKs) treated with difamilast.
RESULTS
RESULTS
We observed increases of intracellular cAMP levels and CREB phosphorylation in difamilast (5 μM)-treated NHEKs. Next, we found that difamilast treatment increased mRNA and protein levels of FLG and LOR in NHEKs. Since reduced expression of keratinocyte proline-rich protein (KPRP) is reported to be involved in skin barrier dysfunction in AD, we examined KPRP expression in difamilast-treated NHEKs. We found that difamilast treatment increased mRNA and protein levels of KPRP in NHEKs. Furthermore, KPRP knockdown using siRNA transfection abolished the upregulation of FLG and LOR in difamilast-treated NHEKs. Finally, CREB knockdown canceled the upregulation of FLG, LOR, and KPRP in difamilast-treated NHEKs, indicating that PDE4 inhibition by difamilast treatment positively regulates FLG and LOR expression via the CREB-KPRP axis in NHEKs.
CONCLUSION
CONCLUSIONS
These findings may provide further guidance for therapeutic strategies in the treatment of AD using difamilast.
Identifiants
pubmed: 37156706
pii: S0923-1811(23)00114-7
doi: 10.1016/j.jdermsci.2023.04.007
pii:
doi:
Substances chimiques
loricrin
0
difamilast
T3U32GLJ0F
Cyclic Nucleotide Phosphodiesterases, Type 4
EC 3.1.4.17
Filaggrin Proteins
0
Intermediate Filament Proteins
0
Proline
9DLQ4CIU6V
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
61-68Informations de copyright
Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Conflict of interest The authors have no conflict of interest to declare.