Regulation of Drug Transporter Expression in Human Hepatocytes Exposed to the Proinflammatory Cytokines Tumor Necrosis Factor-α or Interleukin-6

Abstract

ABSTRACT:Tumor necrosis factor (TNF)-␣ and interleukin (IL)-6 are proinflammatory cytokines known to alter expression of drug transporters in rodent liver. However, their effects toward human hepatic transporters remain poorly characterized. Therefore, this study was designed to analyze the effects of these cytokines on drug transporter expression in primary human hepatocytes. Exposure to 100 ng/ml TNF-␣ or 10 ng/ml IL-6 for 48 h was found to down-regulate mRNA levels of major sinusoidal influx transporters, including sodium-taurocholate cotransporting polypeptide (NTCP), organic anion-transporting polypeptide (OATP) 1B1, OATP1B3, OATP2B1, organic cation transporter (OCT) 1, and organic anion transporter 2. TNF-␣ and IL-6 concomitantly reduced NTCP and OATP1B1 protein expression and NTCP, OATP, and OCT1 transport activities. IL-6, but not TNF-␣, was also found to decrease mRNA expression of the canalicular transporters multidrug resistance 1 gene, multidrug resistance gene-associated protein (MRP) 2, and breast cancer resistance protein (BCRP); it concomitantly decreased MRP2 and BCRP protein expression. TNF-␣, unlike IL-6, markedly reduced bile salt export pump mRNA levels and increased BCRP protein expression. Expression of the sinusoidal MRP3 efflux pump was found to be up-regulated at protein level by both TNF-␣ and IL-6. Taken together, these data show that TNF-␣ and IL-6 similarly altered expression of sinusoidal drug transporters and rather differentially that of canalicular efflux transporters. Such pronounced changes in hepatic transporter expression are likely to contribute to both cholestasis and alterations of pharmacokinetics caused by inflammation in humans.

Alteration of Hepatic but Not Renal Transporter Expression in Diet-Induced Obese Mice

“…ABCC3 also showed an increasing trend, but the blot was not quantified, as some bands were not detectable by software. dmd.aspetjournals.org expression of ABCC2, ABCG2, and ABCB1 (Vee et al, 2009). In livers of DIO mice, interleukin-1␤ was increased compared with that in lean mice, indicating the presence of inflammation, which might affect transporter expression.…”

The Role of Canalicular ABC Transporters in Cholestasis

“…Other transcription factors can also induce ABCG2, and its promoter contains hypoxia, estrogen, progesterone, PPARg, and aryl hydrocarbon receptor response elements (Ebert et al, 2005;Szatmari et al, 2006;Robey et al, 2011;To et al, 2011). Cytokines, growth factors, and micro-RNAs affected gene expression in various ways, whereas promoter methylation increased ABCG2 expression in vitro (Le Vee et al, 2009;Robey et al, 2011).…”

MCF-7 Breast Cancer Cell Line, a Model for the Study of the Association Between Inflammation and ABCG2-Mediated Multi Drug Resistance

“…Glucocorticoides are efficacious in the reducing of chemotherapy adverse side effects and show their intrinsic anticancer activity (Vee et al, 2009) (Pavek et al, 2005). Some glucocorticoids, such as beclomethasone, 6 -methylprednisolone, dexamethasone, and triamcinolone, at micromolar concentrations, are shown to efficiently decrease the transport of ABCG2 substrates (Pavek et al, 2005).…”