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Nitric oxide mediates increased P-glycoprotein activity in interferon-γ-stimulated human intestinal cells
Patients with refractory inflammatory bowel disease (IBD) exhibit increased expression of intestinal P-glycoprotein (P-gp) as well as elevated luminal IFN-γ and nitric oxide (NO) levels. Using the in vitro Caco-2 cell culture model, we investigated whether these pathological mediators associated wit...
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Published in: | American journal of physiology: Gastrointestinal and liver physiology 2005-03, Vol.288 (3), p.G533-G540 |
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Main Authors: | , , , , |
Format: | Article |
Language: | English |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | Patients with refractory inflammatory bowel disease (IBD) exhibit increased expression of intestinal P-glycoprotein (P-gp) as well as elevated luminal IFN-γ 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-γ 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- N
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-(1-iminoethyl)lysine (l-NIL) dramatically reduced production of intracellular NO in response to IFN-γ 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-γ-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-γ and SNAP enhanced DNA binding of NF-κB, whereas inclusion of l-NIL dramatically decreased this cytokine-induced effect on NF-κB binding. These results suggest that NO mediates IFN-γ-induced increase in expression and function of intestinal P-gp in the human Caco-2 cell culture model by altering DNA binding of NF-κB, which may enhance transcription of the ABCB1 gene encoding for this efflux system. |
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ISSN: | 0193-1857 1522-1547 |
DOI: | 10.1152/ajpgi.00248.2004 |