Permeability modulation of human intestinal Caco-2 cell monolayers by interferons.
We investigated the effects of interferon-beta (IFN-beta) and IFN-gamma on the drug efflux activity of the human intestinal Caco-2 cell line, expressing the P-glycoprotein (P-gp) on the apical membrane. The cells grown on Transwell plates were pretreated with 1000U/ml IFN-beta, IFN-gamma or a combination of both for 3 days, and then the transepithelial electrical resistance (TEER) and the vectorial transport of rhodamine-123 (Rho-123) across the cell monolayers were evaluated. Exposure to IFN-gamma reduced substantially the TEER, but the effect of IFN-beta was minimal? The apparent permeability of Rho-123 in both the basolateral-to-apical and apical-to-basolateral directions was significantly increased by IFN-gamma but scarcely by IFN-beta. The combination of IFN-gamma and IFN-beta showed similar effects to IFN-gamma alone. Meanwhile, the cellular uptake of Rho-123 from the apical side was not affected by any IFN treatment. The uptake level was increased approximately three times in the presence of verapamil, a P-gp inhibitor, and the increased level was not affected by any IFN treatment, indicating that the efflux activity mediated by P-gp in the monolayers is not altered by these cytokines. Taken together, these results suggest that IFNs modulate the permeability of Caco-2 monolayer through effect on paracellular transport rather than effect on P-gp activity.
Kawaguchi
Hiroko
H
Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
Akazawa
Yukiko
Y
Watanabe
Yoshihiko
Y
Takakura
Yoshinobu
Y
D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D018938:Caco-2 Cells; D006801:Humans; D007372:Interferons / Q000378:metabolism* / Q000494:pharmacology; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology*; D014700:Verapamil / Q000378:metabolism / Q000494:pharmacology
D007372:Interferons; D014700:Verapamil