Tofacitinib Reprograms Human Monocytes of IBD Patients and Healthy Controls Toward a More Regulatory Phenotype.
Inflamm Bowel Dis
; 26(3): 391-406, 2020 02 11.
Article
in En
| MEDLINE
| ID: mdl-31560043
ABSTRACT
BACKGROUND:
The inhibition of Janus kinases (JAKs) and subsequent signal transducers and activators of transcription (STATs) by tofacitinib represents a new therapeutic strategy in inflammatory bowel diseases (IBD) as clinical trials have led to approval of tofacitinib for ulcerative colitis (UC) and hint at a possible efficacy for Crohn`s disease (CD). However, the impact of tofacitinib on cellular response of monocytes, which are key players in inflammatory responses, has not been investigated so far. We aimed to analyze JAK/STAT-inhibition by tofacitinib in monocytes of IBD patients and healthy controls.METHODS:
Primary monocytes of IBD patients with active disease and healthy controls (n = 18) were analyzed for cytokine expression and phenotype after granulocyte macrophage colony-stimulating factor (GM-CSF)/interferon (IFN)γ-stimulation and tofacitinib pretreatment (1-1000 nM) and capacity to induce Foxp3+-regulatory T cells (Tregs) in cocultures. In total, 20 UC patients and 21 CD patients were included. Additionally, dose-dependent inhibition of JAK/STAT-phosphorylation was analyzed in controls.RESULTS:
Pro-inflammatory costimulation with GM-CSF/IFNγ resulted in significant tumor necrosis factor (TNFα) and interleukin (IL)-6 increase, whereas IL-10 expression decreased in monocytes. Tofacitinib modulated the responses of activated monocytes toward a regulatory phenotype through reduced TNFα and IL-6 secretion and enhanced Treg induction in cocultures. However, in monocytes from active IBD patients, higher tofacitinib dosages were needed for blockade of pro-inflammatory cytokines. Tofacitinib induced stronger regulatory phenotypes in monocytes of UC patients, including more effective inhibition of pro-inflammatory pathways and better restoration of anti-inflammatory mechanisms as compared with CD-derived monocytes.CONCLUSION:
Tofacitinib dose-dependently reprograms monocytes toward a more regulatory cell type. This beneficial effect possibly results from selective JAK/STAT-blockade by adequate tofacitinib dosage with inhibition of pro-inflammatory responses and permission of a balance-shift toward regulatory pathways.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Piperidines
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Pyrimidines
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Monocytes
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Inflammatory Bowel Diseases
/
Granulocyte-Macrophage Colony-Stimulating Factor
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Protein Kinase Inhibitors
Limits:
Adult
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Female
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Humans
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Male
Language:
En
Journal:
Inflamm Bowel Dis
Journal subject:
GASTROENTEROLOGIA
Year:
2020
Document type:
Article
Affiliation country: