Delayed and limited administration of the JAKinib tofacitinib mitigates chronic DSS-induced colitis.
AOM/DSS
JAK inhibitor
anti-inflammatory cytokines
chronic IBD model
effector Treg (eTreg)
pro-inflammatory cytokines
tofacitinib
treatment regimens
Journal
Frontiers in immunology
ISSN: 1664-3224
Titre abrégé: Front Immunol
Pays: Switzerland
ID NLM: 101560960
Informations de publication
Date de publication:
2023
2023
Historique:
received:
03
03
2023
accepted:
25
04
2023
medline:
7
6
2023
pubmed:
5
6
2023
entrez:
5
6
2023
Statut:
epublish
Résumé
In inflammatory bowel disease, dysregulated T cells express pro-inflammatory cytokines. Using a chronic azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colitis model resembling ulcerative colitis, we evaluated whether and when treatment with the Janus kinase (JAK) inhibitor tofacitinib could be curative. Comparing the treatment with two and three cycles of tofacitinib medication in drinking water - intermittently with DSS induction - revealed that two cycles were not only sufficient but also superior over the 3-x regimen. The two cycles of the 2-x protocol paralleled the second and third cycles of the longer protocol. T cells were less able to express interferon gamma (IFN-γ) and the serum levels of IFN-γ, interleukin (IL)-2, IL-6, IL-17, and tumor necrosis factor (TNF) were significantly reduced in sera, while those of IL-10 and IL-22 increased under the 2-x protocol. Likewise, the frequency and effector phenotype of regulatory T cells (Tregs) increased. This was accompanied by normal weight gain, controlled clinical scores, and restored stool consistency. The general and histologic appearance of the colons revealed healing and tissue intactness. Importantly, two phases of tofacitinib medication completely prevented AOM-incited pseudopolyps and the hyper-proliferation of epithelia, which was in contrast to the 3-x regimen. This implies that the initial IBD-induced cytokine expression is not necessarily harmful as long as inflammatory signaling can later be suppressed and that time-restricted treatment allows for anti-inflammatory and tissue-healing cytokine activities.
Identifiants
pubmed: 37275854
doi: 10.3389/fimmu.2023.1179311
pmc: PMC10235777
doi:
Substances chimiques
tofacitinib
87LA6FU830
Piperidines
0
Cytokines
0
Interferon-gamma
82115-62-6
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1179311Informations de copyright
Copyright © 2023 Seal, Schwab, Chiarolla, Hundhausen, Klose, Reu-Hofer, Rosenwald, Wiest and Berberich-Siebelt.
Déclaration de conflit d'intérêts
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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