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Methotrexate modulates tight junctions through NF-κB, MEK, and JNK pathways

Stéphanie Beutheu Youmba1, Liliana Belmonte, Ludovic Galas

  • 1INSERM U1073, Institute for Biomedical Research, IFRMP23, Rouen University, 22 Boulevard Gambetta, Rouen Cedex 1, France.

Journal of Pediatric Gastroenterology and Nutrition
|December 27, 2011
PubMed
Abstract

Insights

Chemotherapy drug methotrexate (MTX) increases intestinal permeability by altering tight junction proteins. Targeting MAPK and NF-κB pathways may mitigate these adverse effects, offering new therapeutic strategies for chemotherapy-induced intestinal mucositis.

Area of Science:

  • Gastroenterology
  • Oncology
  • Molecular Biology

Background:

  • Chemotherapy frequently causes intestinal mucositis, a condition linked to increased intestinal permeability.
  • The precise mechanisms regulating tight junction (TJ) proteins during chemotherapy-induced intestinal damage are not fully understood.

Purpose of the Study:

  • To investigate the regulation of three key TJ proteins—claudin-1, occludin, and zonula occludens-1—in the context of anticancer treatment.
  • To elucidate the molecular pathways involved in chemotherapy-induced alterations of intestinal barrier function.

Main Methods:

  • Methotrexate (MTX) was administered to Sprague-Dawley rats and Caco-2 cell monolayers to induce intestinal mucositis.
  • Western blot and microscopy were used to assess TJ protein expression and distribution.
  • Transepithelial electrical resistance and fluorescein isothiocyanate-dextran flux assays evaluated paracellular permeability in vitro. Cytokine production and signaling pathways were also analyzed.

Main Results:

  • MTX treatment altered TJ protein distribution and reduced claudin-1 and occludin expression in rats during acute mucositis, with recovery observed later.
  • In Caco-2 cells, MTX increased paracellular permeability, associated with altered occludin and zonula occludens-1 expression and distribution.
  • These MTX-induced changes were linked to increased proinflammatory cytokine production and were preventable by inhibiting MEK1/2, JNK, and NF-κB pathways.

Conclusions:

  • MTX treatment increases intestinal permeability through alterations in TJ protein expression and distribution.
  • The observed effects are potentially mediated by MAPK and NF-κB signaling pathways.
  • Targeting these pathways presents a promising strategy to reduce the gastrointestinal side effects of chemotherapy.

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