Cytokines Alter the Expression and Activity of the Multidrug Resistance Transporters in Human Hepatoma Cell Lines; Analysis Using RT‐PCR and cDNA Microarrays

Lee, Gigi; Piquette‐Miller, Micheline

doi:10.1002/jps.10493

Cited by 64 publications

(49 citation statements)

References 29 publications

(34 reference statements)

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“…It is interesting to note that MRP3 has also been shown to be induced at protein levels in human hepatoma HepG2 cells exposed to TNF-␣ (Bohan et al, 2003). By contrast, MRP2 expression, down-regulated in IL-6-exposed primary human hepatocytes, remained unchanged in IL-6-treated human hepatoma HepG2 cells, whereas MDR1/P-glycoprotein expression was decreased in response to TNF-␣ in HepG2 cells (Lee and Piquette-Miller, 2003) but not in primary human hepatocytes. Comparison of ABC transporter regulation in cytokineexposed human hepatocytes with that observed in rodent counterparts also reveals some similarities and some differences: for example, IL-6 decreased MRP2 mRNA levels and failed to significantly alter MRP3 mRNA expression in both primary human hepatocytes and mouse liver, whereas it down-regulated BSEP mRNA levels in mice (Hartmann et al, 2002) but not in human hepatocytes; IL-6 also reduced P-glycoprotein expression in primary rat hepatocytes (Sukhai et al, 2001) but not in human counterparts.…”

Section: Regulation Of Human Hepatic Transporters By Tnf-␣ and Il-6mentioning

confidence: 98%

“…In the same way, treatment of human hepatocytes by IL-1␤ has recently been shown to alter expression of several major hepatic transporters (Le Vee et al, 2008). However, whether TNF-␣ and IL-6 also affect human hepatic transporters remains poorly characterized, even if MDR1 (ABCB1), MRP2, and MRP3 (ABCC3) have been shown to constitute targets for TNF-␣ or IL-6 in some human hepatoma cell lines (Bohan et al, 2003;Lee and Piquette-Miller, 2003).…”

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confidence: 99%

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

Lecureur²,

et al. 2008

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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.

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Section: Regulation Of Human Hepatic Transporters By Tnf-␣ and Il-6mentioning

confidence: 98%

mentioning

confidence: 99%

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

Lecureur²,

et al. 2008

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“…In addition, Ntcp and Mrp2 are also down-regulated in primary rat hepatocytes exposed to IL-1␤ (Denson et al, 2002;Li et al, 2002). However, IL-1␤-mediated regulation of hepatic organic anion transporters remains much less characterized in human hepatocytes than in their rodent counterparts, even if MRP2 (ABCC2) and MRP3 (ABCC3) have been shown to constitute targets of IL-1␤ in certain human hepatoma cell lines (Lee and Piquette-Miller, 2003;Hisaeda et al, 2004). In this context, it is noteworthy that an inverse correlation between sodium-taurocholate cotransporting polypeptide (NTCP) (SLC10A1) mRNA levels and IL-1␤ secretion has been recently reported in human liver slices exposed to lipopolysaccharide (LPS) (Elferink et al, 2004), suggesting that at least some human organic anion transporters, especially NTCP, may be downregulated by IL-1␤, as their rodent counterparts.…”

mentioning

confidence: 99%

Down-Regulation of Organic Anion Transporter Expression in Human Hepatocytes Exposed to the Proinflammatory Cytokine Interleukin 1β

Vée¹,

Gripon²,

Stieger³

et al. 2007

Drug Metab Dispos

114

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ABSTRACT:Interleukin (IL) 1␤ is a proinflammatory cytokine known to markedly alter expression of major organic anion transporters in rodent hepatocytes. However, its effects toward human hepatic transporters remain poorly characterized. Therefore, the present study was aimed at determining IL-1␤ effects on expression of organic anion transporters in primary human hepatocytes and highly differentiated human hepatoma HepaRG cells. Exposure to 1 ng/ml IL-1␤ was first shown to markedly repress mRNA expression of sodium-taurocholate cotransporting polypeptide (NTCP), a major sinusoidal transporter handling bile acids, in both human hepatocytes and HepaRG cells. Interleukin (IL) 1␤, a major proinflammatory cytokine contributing to endotoxin-or sepsis-induced cholestasis in liver, impairs hepatic detoxification pathways (Prandota, 2005;Aitken et al., 2006). Thus, IL-1␤ decreases expression of various drug-metabolizing enzymes, including cytochromes P450 and glutathione S-transferases, in human and rat hepatocytes (Abdel-Razzak et al., 1993;Maheo et al., 1997). In addition, it interferes with drug-related regulation of detoxifying proteins (Assenat et al., 2004).Organic anion transporters handling bile acids or drugs also constitute important targets of IL-1␤ in rodents (Geier et al., 2007;Petrovic et al., 2007). Indeed, IL-1␤-treated mice display reduced expression of various hepatic transporters, including solute carrier (SLC) proteins like sinusoidal sodium-dependent taurocholate transporter Ntcp (Slc10a1) and organic anion transporting polypeptides (Oatp) 1 (Slco1a1) and Oatp2 (Slco1a2), and ATP binding cassette (ABC) transporters like bile salt export pump (Bsep) (Abcb11) and multidrug resistance-associated protein (Mrp) 2 (Abcc2) (Hartmann et al., 2002;Geier et al., 2005). In addition, Ntcp and Mrp2 are also down-regulated in primary rat hepatocytes exposed to IL-1␤ (Denson et al., 2002;Li et al., 2002). However, IL-1␤-mediated regulation of hepatic organic anion transporters remains much less characterized in human hepatocytes than in their rodent counterparts, even if MRP2 (ABCC2) and MRP3 (ABCC3) have been shown to constitute targets of IL-1␤ in certain human hepatoma cell lines (Lee and Piquette-Miller, 2003;Hisaeda et al., 2004). In this context, it is noteworthy that an inverse correlation between sodium-taurocholate cotransporting polypeptide (NTCP) (SLC10A1) mRNA levels and IL-1␤ secretion has been recently reported in human liver slices exposed to lipopolysaccharide (LPS) (Elferink et al., 2004), suggesting that at least some human organic anion transporters, especially NTCP, may be downregulated by IL-1␤, as their rodent counterparts. The present study was designed to investigate this hypothesis. Using human primary hepatocytes and human highly differentiated hepatoma HepaRG cells, well recognized as convenient models for studying regulation of transporters Le Vee et al., 2006), we report that IL-1␤ treatment markedly reduced functional expression of NTCP in human hepatocytes; mRNA levels of other major ...

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“…Microbial inflammatory activation is also associated with increased placental cytokine expression (Saji et al, 2000). The effects of cytokines on human placental ABC transporter expression have not been studied to date, although findings from other tissues (Lee and Piquette-Miller, 2003;Belliard et al, 2004) and animal models (Wang et al, 2005) would suggest that TNF-␣, IL-1␤, and IL-6 could decrease the expression of MDR1, whereas IL-6 may stimulate MRP1 expression. There are insufficient data to base any prediction of the effects of cytokines on MDR3 and BCRP expression.…”

mentioning

confidence: 99%

Independent Regulation of Apical and Basolateral Drug Transporter Expression and Function in Placental Trophoblasts by Cytokines, Steroids, and Growth Factors

Evseenko

Paxton²,

Keelan³

2007

Drug Metab Dispos

166

135

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ABSTRACT:Placental ATP binding cassette (ABC) transporters protect placental and fetal tissues by effluxing xenobiotics and endogenous metabolites. We have investigated the effects of cytokines and survival/growth factors, implicated in various placental pathologies, on ABC transporter expression and function in primary placental trophoblast cells. Treatment of primary term trophoblasts in vitro with tumor necrosis factor-␣ (TNF-␣) or interleukin (IL)-1␤ decreased mRNA and protein expression of apical transporters ABCB1/multidrug resistance gene product 1 (MDR1) and ABCG2/ breast cancer resistance protein (BCRP) protein by 40 to 50% (P < 0.05). In contrast, IL-6 increased mRNA and protein expression of the basolateral transporter ABCB4/MDR3 (P < 0.05), whereas ABCC1/MRP1 expression was unaltered. Pretreatment of trophoblasts with TNF-␣ over 48 h resulted in significantly decreased BCRP efflux activity (increased mitoxantrone accumulation) with minimal changes in MDR1/3 activity. Epidermal growth factor (EGF) and insulin-like growth factor II, on the other hand, significantly increased BCRP expression at the mRNA and protein level (P < 0.05); EGF treatment also increased BCRP functional activity. Estradiol stimulated BCRP, MDR1, and MDR3 mRNA and protein expression by 40 to 60% and increased MDR1/3 functional activity (P < 0.05). Progesterone had modest positive effects on MRP1 mRNA and MDR1 protein expression (P < 0.05). In conclusion, this study shows that proinflammatory cytokines, sex steroids, and growth factors exert independent effects on expression of apical and basolateral placental ABC transporters in primary trophoblast. Such changes could alter placental drug disposition, increase fetal susceptibility to toxic xenobiotics, and impact on placental viability and function.

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Cytokines Alter the Expression and Activity of the Multidrug Resistance Transporters in Human Hepatoma Cell Lines; Analysis Using RT‐PCR and cDNA Microarrays

Cited by 64 publications

References 29 publications

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

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

Down-Regulation of Organic Anion Transporter Expression in Human Hepatocytes Exposed to the Proinflammatory Cytokine Interleukin 1β

Independent Regulation of Apical and Basolateral Drug Transporter Expression and Function in Placental Trophoblasts by Cytokines, Steroids, and Growth Factors

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