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Original Article
- Restoration of colonic barrier function by tofacitinib in experimental colitis: anti-inflammatory effects and decreased expression of claudins-2 and claudin-15
- Humberto Barbosa da Costa Filho, Gerardo Autran Cavalcante Araújo, Thiago Meneses Araújo Leite Sales, Suliana Mesquita Paula, Marco Antonio de Freitas Clementino, Alexandre Havt, Pedro Marcos Gomes Soares, Marcellus Henrique Loiola Ponte Souza
- Received November 18, 2024 Accepted February 9, 2025 Published online March 31, 2025
- DOI: https://doi.org/10.5217/ir.2024.00186 [Epub ahead of print]
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Abstract
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ePub - Background/Aims
Inflammatory bowel disease can be triggered by disturbances in intestinal mucosal integrity, leading to bacterial transmigration. The treatment of inflammatory bowel diseases must not only aim to reduce inflammation, but also to reverse the damage to mucosal barrier function. Janus kinase (JAK) inhibitors have been used to treat inflammatory diseases, including ulcerative colitis. However, little is known about the ability of this class of drugs to reverse the loss of mucosal integrity. This study evaluated the effects of tofacitinib, a JAK pathway inhibitor, on inflammation and colonic mucosal integrity in a rat model of 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis.
Methods
Colitis was induced in Wistar rats via rectal administration of TNBS (20 mg+50% ethanol). The control group received only saline. The animals were pretreated with tofacitinib (15 mg/kg) or saline 30 minutes before induction and twice daily thereafter. Seven days after induction, the animals were euthanized, the colon was removed, and myeloperoxidase activity, baseline transepithelial electrical resistance (TER), TER after 1 hour, and fluorescein permeability were assessed. Tight junction proteins in the colon (claudin-2, claudin-15, and tricellulin) were detected using Western blotting.
Results
Tofacitinib treatment significantly reduced (P< 0.05) the inflammatory parameters and preserved the integrity of the intestinal epithelial barrier compared with the colitis group (P< 0.05), increased baseline TER, reduced the drop in TER after 1 hour, and decreased paracellular permeability to fluorescein by reducing claudin-2 and claudin-15 expression.
Conclusions
JAK inhibition by tofacitinib restored colonic barrier function through antiinflammatory effects and decreased claudin-2 and claudin-15 expressions.
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