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

被引:21
|
作者
Dixit, SG
Zingarelli, B
Buckley, DJ
Buckley, AR
Pauletti, GM
机构
[1] Univ Cincinnati, Coll Pharm, Div Pharmaceut Sci, Cincinnati, OH 45267 USA
[2] Childrens Hosp Med Ctr, Div Crit Care, Cincinnati, OH USA
来源
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY | 2005年 / 288卷 / 03期
关键词
Caco-2; cells; cytokines; efflux systems; signal transduction pathways;
D O I
10.1152/ajpgi.00248.2004
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
Patients with refractory inflammatory bowel disease (IBD) exhibit increased expression of intestinal P-glycoprotein (P-gp) as well as elevated luminal IFN-gamma 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-gamma 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-6-(1-iminoethyl)-lysine (L-NIL) dramatically reduced production of intracellular NO in response to IFN-gamma 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-gamma-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-gamma and SNAP enhanced DNA binding of NF-kappaB, whereas inclusion of L-NIL dramatically decreased this cytokine-induced effect on NF-kappaB binding. These results suggest that NO mediates IFN-gamma-induced increase in expression and function of intestinal P-gp in the human Caco-2 cell culture model by altering DNA binding of NF-kappaB, which may enhance transcription of the ABCB1 gene encoding for this efflux system.
引用
收藏
页码:G533 / G540
页数:8
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