Interleukin-23 drives expansion of Thelper 17 cells through epigenetic regulation by signal transducer and activators of transcription 3 in lupus patients.
Azetidines
/ pharmacology
CD4-Positive T-Lymphocytes
/ drug effects
Cell Proliferation
/ drug effects
Chromatin Immunoprecipitation
/ methods
Epigenesis, Genetic
Flow Cytometry
Gene Expression
Humans
Interleukin-12
/ pharmacology
Interleukin-23
/ pharmacology
Interleukins
/ pharmacology
Jumonji Domain-Containing Histone Demethylases
/ metabolism
Lupus Erythematosus, Systemic
/ blood
Nuclear Receptor Subfamily 1, Group F, Member 3
/ genetics
Phosphorylation
Purines
/ pharmacology
Pyrazoles
/ pharmacology
Real-Time Polymerase Chain Reaction
/ methods
STAT3 Transcription Factor
/ blood
STAT4 Transcription Factor
/ metabolism
Signal Transduction
Sulfonamides
/ pharmacology
Th17 Cells
/ drug effects
IL-23
Th17 cells
baricitinib
signal transducer and activator of transcription
systemic lupus erythematosus
Journal
Rheumatology (Oxford, England)
ISSN: 1462-0332
Titre abrégé: Rheumatology (Oxford)
Pays: England
ID NLM: 100883501
Informations de publication
Date de publication:
01 10 2020
01 10 2020
Historique:
received:
24
08
2019
revised:
15
03
2020
pubmed:
7
5
2020
medline:
23
1
2021
entrez:
7
5
2020
Statut:
ppublish
Résumé
To elucidate the molecular mechanisms underlying pathogenic Th17 cells, we investigated the modulation of epigenetic modifications and its association with SLE. Naive CD4+ T cells were cultured in Th17 polarizing conditions for 5 days and then treated with various cytokines, including IL-23. Expression of Th17 cell-related markers and phosphorylation of signal transducers and activators of transcription (pSTATs) were analysed using flow cytometry and quantitative PCR. Histone modifications were assessed using chromatin immunoprecipitation PCR. T cell phenotypes and pSTATs were analysed in blood samples of patients with SLE (n = 28). Finally, the effects of baricitinib on memory Th17 cells were investigated in SLE patients (n = 12). Stimulation of resting Th17 cells with IL-23 promoted maturation of these cells (P < 0.0001). IL-23 induced pSTAT3, but not pSTAT4, during Th17 cell maturation (P < 0.05). IL-23-induced STAT3 directly bound the RORγT gene locus. This was accompanied by induction of the H3H4me3 permissive mark and reduction of the H3K27me3 repressive mark, leading to enhanced RORγT gene expression. IL-23-induced expansion of Th17 cells and pSTAT3 were suppressed by the addition of baricitinib in a concentration-dependent manner (P < 0.05). In memory Th17 cells from SLE patients, pSTAT3 was hypersensitized by IL-23 stimulation and inhibited by baricitinib (P < 0.05). The results of this study indicate that IL-23/STAT3 signalling plays a fundamental role in Th17 cell maturation through transcriptional and epigenetic modifications in patients with SLE. This mechanism may underlie pathogenic Th17 cell expansion and may lead to identification of novel therapeutic targets for SLE.
Identifiants
pubmed: 32375179
pii: 5831398
doi: 10.1093/rheumatology/keaa176
doi:
Substances chimiques
Azetidines
0
Interleukin-23
0
Interleukins
0
Nuclear Receptor Subfamily 1, Group F, Member 3
0
Purines
0
Pyrazoles
0
RORC protein, human
0
STAT3 Transcription Factor
0
STAT3 protein, human
0
STAT4 Transcription Factor
0
STAT4 protein, human
0
Sulfonamides
0
Interleukin-12
187348-17-0
Jumonji Domain-Containing Histone Demethylases
EC 1.14.11.-
baricitinib
ISP4442I3Y
interleukin-21
MKM3CA6LT1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3058-3069Informations de copyright
© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.