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Interleukin-18 Down-Regulates Multidrug Resistance-Associated Protein 2 Expression through Farnesoid X Receptor Associated with Nuclear Factor Kappa B and Yin Yang 1 in Human Hepatoma HepG2 Cells.

Liu XC, Lian W, Zhang LJ, Feng XC, Gao Y, Li SX, Liu C, Cheng Y, Yang L, Wang XJ, Chen L, Wang RQ, Chai J, Chen WS - PLoS ONE (2015)

Bottom Line: Furthermore, the activated NF-κB pathway increased YY1 and reduced FXR.The reduced expression of FXR and MRP2 in HepG2 cells that had been caused by IL-18 treatment was also attenuated by YY1 knockdown.We further observed significantly elevated IL-18, NF-κB, and YY1 expression and decreased FXR and MRP2 expression in bile duct-ligated Sprague Dawley rat livers.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing, People's Republic of China; Department of Gastroenterology, Chengdu Military General Hospital, Chengdu, Sichuan, People's Republic of China.

ABSTRACT
Multidrug resistance-associated protein 2 (MRP2) plays an important role in bile acid metabolism by transporting toxic organic anion conjugates, including conjugated bilirubin, glutathione, sulfate, and multifarious drugs. MRP2 expression is reduced in cholestatic patients and rodents. However, the molecular mechanism of MRP2 down-regulation remains elusive. In this report, we treated human hepatoma HepG2 cells with interleukin-18 (IL-18) and measured the expression of MRP2, nuclear factor kappa B (NF-κB), farnesoid X receptor (FXR), and the transcription factor Yin Yang 1 (YY1) by quantitative real-time quantitative polymerase chain reaction (PCR) and western blotting. We found that expression of MRP2 was repressed by IL-18 at both the mRNA and protein levels in a dose- and time-dependent manner. Furthermore, the activated NF-κB pathway increased YY1 and reduced FXR. These changes were all attenuated in HepG2 cells with knockdown of the NF-κB subunit, p65. The reduced expression of FXR and MRP2 in HepG2 cells that had been caused by IL-18 treatment was also attenuated by YY1 knockdown. We further observed significantly elevated IL-18, NF-κB, and YY1 expression and decreased FXR and MRP2 expression in bile duct-ligated Sprague Dawley rat livers. Chromatin immunoprecipitation assays also showed that FXR bound to the promoter region in MRP2 was less abundant in liver extracts from bile duct-ligated rats than sham-operated rats. Our findings indicate that IL-18 down-regulates MRP2 expression through the nuclear receptor FXR in HepG2 cells, and may be mediated by NF-κB and YY1.

No MeSH data available.


Related in: MedlinePlus

Model of the mechanism of IL-18 induced reduction in MRP2 expression.When HepG2 cells were treated with IL-18, NF-κB is activated, which in turn increases transcription factor YY1 expression; enhanced YY1 decreases FXR expression, then leads to the reduction of MRP2 expression. (+), activation; (-), inhibition; IL-18R, IL-18 receptor; IκB, I kappa B; Ⓟ, phosphorylation.
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pone.0136215.g007: Model of the mechanism of IL-18 induced reduction in MRP2 expression.When HepG2 cells were treated with IL-18, NF-κB is activated, which in turn increases transcription factor YY1 expression; enhanced YY1 decreases FXR expression, then leads to the reduction of MRP2 expression. (+), activation; (-), inhibition; IL-18R, IL-18 receptor; IκB, I kappa B; Ⓟ, phosphorylation.

Mentions: In summary, our data demonstrate that IL-18 can up-regulate the expression of YY1 through the NF-κB signaling pathway. We suggest a model where elevated YY1 expression suppresses FXR expression, leading to the decrease of MRP2 expression (Fig 7). Our findings represent a novel negative regulation of MRP2, which may contribute to increased understanding of the decreased expression of MRP2 in cholestasis and may also provide new directions to explore in the development of novel therapeutic strategies for clinical treatment of cholestasis.


Interleukin-18 Down-Regulates Multidrug Resistance-Associated Protein 2 Expression through Farnesoid X Receptor Associated with Nuclear Factor Kappa B and Yin Yang 1 in Human Hepatoma HepG2 Cells.

Liu XC, Lian W, Zhang LJ, Feng XC, Gao Y, Li SX, Liu C, Cheng Y, Yang L, Wang XJ, Chen L, Wang RQ, Chai J, Chen WS - PLoS ONE (2015)

Model of the mechanism of IL-18 induced reduction in MRP2 expression.When HepG2 cells were treated with IL-18, NF-κB is activated, which in turn increases transcription factor YY1 expression; enhanced YY1 decreases FXR expression, then leads to the reduction of MRP2 expression. (+), activation; (-), inhibition; IL-18R, IL-18 receptor; IκB, I kappa B; Ⓟ, phosphorylation.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4546195&req=5

pone.0136215.g007: Model of the mechanism of IL-18 induced reduction in MRP2 expression.When HepG2 cells were treated with IL-18, NF-κB is activated, which in turn increases transcription factor YY1 expression; enhanced YY1 decreases FXR expression, then leads to the reduction of MRP2 expression. (+), activation; (-), inhibition; IL-18R, IL-18 receptor; IκB, I kappa B; Ⓟ, phosphorylation.
Mentions: In summary, our data demonstrate that IL-18 can up-regulate the expression of YY1 through the NF-κB signaling pathway. We suggest a model where elevated YY1 expression suppresses FXR expression, leading to the decrease of MRP2 expression (Fig 7). Our findings represent a novel negative regulation of MRP2, which may contribute to increased understanding of the decreased expression of MRP2 in cholestasis and may also provide new directions to explore in the development of novel therapeutic strategies for clinical treatment of cholestasis.

Bottom Line: Furthermore, the activated NF-κB pathway increased YY1 and reduced FXR.The reduced expression of FXR and MRP2 in HepG2 cells that had been caused by IL-18 treatment was also attenuated by YY1 knockdown.We further observed significantly elevated IL-18, NF-κB, and YY1 expression and decreased FXR and MRP2 expression in bile duct-ligated Sprague Dawley rat livers.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing, People's Republic of China; Department of Gastroenterology, Chengdu Military General Hospital, Chengdu, Sichuan, People's Republic of China.

ABSTRACT
Multidrug resistance-associated protein 2 (MRP2) plays an important role in bile acid metabolism by transporting toxic organic anion conjugates, including conjugated bilirubin, glutathione, sulfate, and multifarious drugs. MRP2 expression is reduced in cholestatic patients and rodents. However, the molecular mechanism of MRP2 down-regulation remains elusive. In this report, we treated human hepatoma HepG2 cells with interleukin-18 (IL-18) and measured the expression of MRP2, nuclear factor kappa B (NF-κB), farnesoid X receptor (FXR), and the transcription factor Yin Yang 1 (YY1) by quantitative real-time quantitative polymerase chain reaction (PCR) and western blotting. We found that expression of MRP2 was repressed by IL-18 at both the mRNA and protein levels in a dose- and time-dependent manner. Furthermore, the activated NF-κB pathway increased YY1 and reduced FXR. These changes were all attenuated in HepG2 cells with knockdown of the NF-κB subunit, p65. The reduced expression of FXR and MRP2 in HepG2 cells that had been caused by IL-18 treatment was also attenuated by YY1 knockdown. We further observed significantly elevated IL-18, NF-κB, and YY1 expression and decreased FXR and MRP2 expression in bile duct-ligated Sprague Dawley rat livers. Chromatin immunoprecipitation assays also showed that FXR bound to the promoter region in MRP2 was less abundant in liver extracts from bile duct-ligated rats than sham-operated rats. Our findings indicate that IL-18 down-regulates MRP2 expression through the nuclear receptor FXR in HepG2 cells, and may be mediated by NF-κB and YY1.

No MeSH data available.


Related in: MedlinePlus