ST18 affects cell-cell adhesion in pemphigus vulgaris in a tumour necrosis factor-α-dependent fashion.
Journal
The British journal of dermatology
ISSN: 1365-2133
Titre abrégé: Br J Dermatol
Pays: England
ID NLM: 0004041
Informations de publication
Date de publication:
06 2021
06 2021
Historique:
accepted:
12
11
2020
pubmed:
19
11
2020
medline:
2
7
2021
entrez:
18
11
2020
Statut:
ppublish
Résumé
Pemphigus vulgaris (PV) is a life-threatening mucocutaneous autoimmune blistering disease. We previously showed that genetic variants within the ST18 gene promoter area confer a sixfold increase in the propensity to develop PV. ST18, a transcription factor, was found to be overexpressed in the epidermis of patients with PV. In addition, it was found to promote autoantibody-mediated abnormal epidermal cell-cell adhesion and secretion of proinflammatory mediators by keratinocytes. To delineate the mechanism through which ST18 contributes to destabilization of cell-cell adhesion. We used quantitative reverse-transcriptase polymerase chain reaction, immunofluorescence microscopy, a luciferase reporter system, site-directed mutagenesis, chromatin immunoprecipitation (ChIP) and the dispase dissociation assay. The ChIP and luciferase reporter assays showed that ST18 directly binds and activates the TNF promoter. Accordingly, increased ST18 expression contributes to PV pathogenesis by destabilizing cell-cell adhesion in a tumour necrosis factor (TNF)-α-dependent fashion. In addition, dual immunofluorescence staining showed increased expression of both ST18 and TNF-α in the skin of patients with PV carrying an ST18-associated PV risk variant, which was found to be associated with a more extensive PV phenotype. Our findings suggest a role for TNF-α in mediating the deleterious effect of increased ST18 expression in PV skin.
Sections du résumé
BACKGROUND
Pemphigus vulgaris (PV) is a life-threatening mucocutaneous autoimmune blistering disease. We previously showed that genetic variants within the ST18 gene promoter area confer a sixfold increase in the propensity to develop PV. ST18, a transcription factor, was found to be overexpressed in the epidermis of patients with PV. In addition, it was found to promote autoantibody-mediated abnormal epidermal cell-cell adhesion and secretion of proinflammatory mediators by keratinocytes.
OBJECTIVES
To delineate the mechanism through which ST18 contributes to destabilization of cell-cell adhesion.
METHODS
We used quantitative reverse-transcriptase polymerase chain reaction, immunofluorescence microscopy, a luciferase reporter system, site-directed mutagenesis, chromatin immunoprecipitation (ChIP) and the dispase dissociation assay.
RESULTS
The ChIP and luciferase reporter assays showed that ST18 directly binds and activates the TNF promoter. Accordingly, increased ST18 expression contributes to PV pathogenesis by destabilizing cell-cell adhesion in a tumour necrosis factor (TNF)-α-dependent fashion. In addition, dual immunofluorescence staining showed increased expression of both ST18 and TNF-α in the skin of patients with PV carrying an ST18-associated PV risk variant, which was found to be associated with a more extensive PV phenotype.
CONCLUSIONS
Our findings suggest a role for TNF-α in mediating the deleterious effect of increased ST18 expression in PV skin.
Substances chimiques
Autoantibodies
0
Desmoglein 3
0
Repressor Proteins
0
ST18 protein, human
0
Tumor Necrosis Factor-alpha
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1153-1160Subventions
Organisme : Israel Ministry of Health
Organisme : Ram family foundation
Organisme : Maurice Kahn Foundation
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2020 British Association of Dermatologists.
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