Tofacitinib Reprograms Human Monocytes of IBD Patients and Healthy Controls Toward a More Regulatory Phenotype
| Autor: | Eva Lenker, Hartmut Schmidt, Christoph Kessel, Friederike Cordes, Dominik Bettenworth, Toni Weinhage, Dirk Foell, Lea J Spille, Georg Varga |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Adult
Male 0301 basic medicine medicine.medical_treatment Inflammatory bowel disease Monocytes 03 medical and health sciences 0302 clinical medicine Piperidines medicine Humans Immunology and Allergy Protein Kinase Inhibitors Cells Cultured Tofacitinib business.industry Gastroenterology Granulocyte-Macrophage Colony-Stimulating Factor Interleukin FOXP3 Inflammatory Bowel Diseases medicine.disease Phenotype Pyrimidines 030104 developmental biology Granulocyte macrophage colony-stimulating factor Cytokine Immunology Cytokines Female 030211 gastroenterology & hepatology Tumor necrosis factor alpha Janus kinase business Signal Transduction medicine.drug |
| Zdroj: | Inflammatory Bowel Diseases. 26:391-406 |
| ISSN: | 1536-4844 1078-0998 |
| DOI: | 10.1093/ibd/izz213 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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