The effect of interleukin-4 (IL-4), a cytokine associated with allergy and inflammation, on the permeability of the intestinal epithelium was investigated. IL-4 reduced transepithelial electrical resistance (TER) and increased permeation to horseradish peroxidase (HRP) and Lucifer Yellow (LY) of human intestinal T84 cell monolayers. The increased permeation due to IL-4 treatment was also observed at 4 degrees C. The permeability of T84 cell monolayers to beta-lactogulobulin (beta-Lg), ovalbumin (OVA), and fluorescein isothiocyanate (FITC)-dextran of various molecular sizes was also high in the IL-4-treated cell monolayers. Sodium azide (NaN(3)), which inhibits ATP synthesis of the cells, did not inhibit the increases in these substances. Even 150 kDa FITC-dextran significantly permeated the T84 cells when the monolayers were treated with IL-4. These results suggest that fairly large molecules are able to permeate intestinal epithelial monolayers via the energy-independent paracellular pathway when the monolayers are exposed to excessive IL-4.