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The Effect of JAK‐Inhibitor Tofacitinib on Intestinal Epithelial Barrier Function
Author(s) -
Sayoc Anica,
Krishnan Moorthy,
McCole Declan F.
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1017.5
Subject(s) - tofacitinib , pharmacology , medicine , janus kinase , ulcerative colitis , cytokine , rheumatoid arthritis , disease
Tofacitinib is an FDA‐approved oral Janus kinase (JAK) inhibitor that modulates the JAK‐STAT signaling cascade activated by inflammatory cytokines, and has shown clinical benefit in trials on ulcerative colitis (UC) patients. However, the effect of this drug on intestinal epithelial cells (IEC) and intestinal permeability, which is increased in UC, has not been elucidated. The aim of this study was to determine if tofacitinib can reduce IEC permeability caused by the inflammatory cytokine, IFN‐γMethods T 84 intestinal epithelial cell lines were cultured on transwells for 12–13 days. Preventive effects of tofacitinib were determined by pre‐treatment with tofacitinib (50μM) apically (to mimic oral administration to patients) for 1 hour followed by basolateral administration of IFN‐γ (1000U/ml) for 24 hours. The concentration of tofacitinib was based on a dose response (2μM, 10μM, 50μM) study on transepithelial electrical resistance (TEER) upon IFN‐γ challenge. Therapeutic effects of tofacitinib were studied by treating T 84 cells twice with tofacitinib (16.7μM) at 6 and 18 hours post‐IFN‐γ treatment (1000U/ml). Timing and dosage of tofacitinib were chosen from post‐IFN‐γ dose‐response studies. TEER and 4kD FITC‐dextran permeability were measured to indicate changes in paracellular permeability to ion flux and macromolecules, respectively. Results Tofacitinib prevented IFN‐γ‐induced increases in TEER (p<0.001; n=3) and 4kD FITC‐dextran permeability in IECs and maintained the barrier integrity at levels comparable to untreated and vehicle (DMSO)‐treated controls. Although one dose of tofacitinib 24 hours post‐IFN‐γ had no effect on TEER, administration of tofacitinib at two time points after IFN‐γ partially rescued IECs from the effect of IFN‐γ on TEER and 4kD FITC‐dextran permeability compared to untreated and vehicle‐treated controls. These data indicate that tofacitinib can restrict intestinal epithelial barrier defects induced by an inflammatory cytokine. This may potentially contribute to the beneficial effects of tofacitinib observed in clinical trials in UC patients. Support or Funding Information Supported by NIH R01 DK091281 (DFM)