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This Article Full Text Full Text (PDF) All Versions of this Article: 288/3/G533    most recent 00248.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (5) Citing Articles via Google Scholar Google Scholar Articles by Dixit, S. G. Articles by Pauletti, G. M. Search for Related Content PubMed PubMed Citation Articles by Dixit, S. G. Articles by Pauletti, G. M.

INFLAMMATION/IMMUNITY/MEDIATORS

Nitric oxide mediates increased P-glycoprotein activity in interferon--stimulated human intestinal cells

¹Division of Pharmaceutical Sciences, College of Pharmacy, University of Cincinnati, Cincinnati; and ²Children's Hospital Medical Center, Division of Critical Care, Cincinnati, Ohio

Submitted 3 June 2004 ; accepted in final form 10 October 2004

Patients with refractory inflammatory bowel disease (IBD) exhibit increased expression of intestinal P-glycoprotein (P-gp) as well as elevated luminal IFN- and nitric oxide (NO) levels. Using the in vitro Caco-2 cell culture model, we investigated whether these pathological mediators associated with the etiology of IBD affect functional activity of intestinal efflux systems. IFN- reduced cellular uptake of cyclosporin A (CysA) but not methotrexate (MTX) in a time- and concentration-dependent manner. Simultaneously, P-gp expression increased by approximately twofold. Coincubation with the inducible NO synthase inhibitor L-N⁶-(1-iminoethyl)lysine (L-NIL) dramatically reduced production of intracellular NO in response to IFN- stimulus. The presence of L-NIL also abrogated the cytokine-mediated increase in P-gp expression and function suggesting that NO is required for IFN--mediated activation of this efflux system. Exposure of Caco-2 cells to the chemical NO donor S-nitroso-N-acetylpenicillamine (SNAP) produced a concentration-dependent decrease in intracellular CysA accumulation that was paralleled by an increase in P-gp expression. Both IFN- and SNAP enhanced DNA binding of NF-B, whereas inclusion of L-NIL dramatically decreased this cytokine-induced effect on NF-B binding. These results suggest that NO mediates IFN--induced increase in expression and function of intestinal P-gp in the human Caco-2 cell culture model by altering DNA binding of NF-B, which may enhance transcription of the ABCB1 gene encoding for this efflux system.

Caco-2 cells; cytokines; efflux systems; signal transduction pathways