Pregnane X Receptor Modulates the Inflammatory Response in Primary Cultures of Hepatocytes

Sun, Mengxi; Cui, Wenqi; Woody, Sarah K.; Staudinger, Jeff

doi:10.1124/dmd.114.062307

Cited by 50 publications

(48 citation statements)

References 55 publications

(72 reference statements)

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“…Expression of exogenous PXR significantly increased the basal levels of TNFa messenger RNA by approximately 8-fold when compared with vehicletreated nontransduced PXR-KO hepatocytes. This is consistent with our previous publication that indicates that hepatocytes lacking PXR exhibit a diminished capacity to mount a robust immune response following challenge with a lipopolysaccharide (Sun et al, 2015). Hepatocytes expressing exogenous PXR that were cotreated with TNFa and rifampicin together exhibited significant repression of TNFainducible TNFa messenger RNA expression.…”

Section: Sumoylation and Ubiquitylation Of Pregnane X Receptorsupporting

confidence: 81%

“…Previous research from our laboratory and others indicates that PXR activation can suppress the cytokine-inducible expression of TNFa and interleukin 6 (IL-6) in the liver and intestine (Teng and PiquetteMiller, 2005;Shah et al, 2007;Hu et al, 2010;Dou et al, 2012;Koutsounas et al, 2013;Sun et al, 2015). We therefore examined the role of PIAS1 in promoting this effect in a PXR-dependent manner in the liver.…”

Section: Pxr Is the Molecular Target Of Both The Sumo-andmentioning

confidence: 99%

“…However, clinical treatment with PXR activators can also lead to the repression or attenuation of other biochemical pathways, including the inflammatory response in the liver and intestine (Moreau et al, 2008). It is now well accepted that activation of PXR is associated with general suppression of the inflammatory response in these tissues (Shah et al, 2007;Cheng et al, 2012;Dou et al, 2012Dou et al, , 2014Sun et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

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SUMOylation and Ubiquitylation Circuitry Controls Pregnane X Receptor Biology in Hepatocytes

et al. 2015

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Several nuclear receptor (NR) superfamily members are known to be the molecular target of either the small ubiquitin-related modifier (SUMO) or ubiquitin-signaling pathways. However, little is currently known regarding how these two post-translational modifications interact to control NR biology. We show that SUMO and ubiquitin circuitry coordinately modifies the pregnane X receptor (PXR, NR1I2) to play a key role in regulating PXR protein stability, transactivation capacity, and transcriptional repression. The SUMOylation and ubiquitylation of PXR is increased in a ligand-and tumor necrosis factor alpha-dependent manner in hepatocytes. The SUMO-E3 ligase enzymes protein inhibitor of activated signal transducer and activator of transcription-1 (STAT1) STAT-1 (PIAS1) and protein inhibitor of activated STAT Y (PIASy) drive high levels of PXR SUMOylation. Expression of protein inhibitor of activated stat 1 selectively increases SUMO(3)ylation as well as PXR-mediated induction of cytochrome P450, family 3, subfamily A and the xenobiotic response.The PIASy-mediated SUMO(1)ylation imparts a transcriptionally repressive function by ameliorating interaction of PXR with coactivator protein peroxisome proliferator-activated receptor gamma coactivator-1-alpha. The SUMO modification of PXR is effectively antagonized by the SUMO protease sentrin protease (SENP) 2, whereas SENP3 and SENP6 proteases are highly active in the removal of SUMO2/3 chains. The PIASy-mediated SUMO(1)ylation of PXR inhibits ubiquitin-mediated degradation of this important liverenriched NR by the 26S proteasome. Our data reveal a working model that delineates the interactive role that these two post-translational modifications play in reconciling PXR-mediated gene activation of the xenobiotic response versus transcriptional repression of the proinflammatory response in hepatocytes. Taken together, our data reveal that the SUMOylation and ubiquitylation of the PXR interface in a fundamental manner directs its biologic function in the liver in response to xenobiotic or inflammatory stress.

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Section: Sumoylation and Ubiquitylation Of Pregnane X Receptorsupporting

confidence: 81%

Section: Pxr Is the Molecular Target Of Both The Sumo-andmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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SUMOylation and Ubiquitylation Circuitry Controls Pregnane X Receptor Biology in Hepatocytes

et al. 2015

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“…It has been shown that the expression of ABC transporter MDR1 and MRP2 is induced by rifampicin via PXR and CAR nuclear receptors [25]. As a consequence, we investigated the involvement of nuclear receptors such as PXR, CAR, AhR and RXRα in regulation of SLC transporters by rifampicin.…”

Section: Rifampicin Regulates Ahr and Rxra Expression In Human Skinmentioning

confidence: 99%

Characterization of SLC transporters in human skin

Alriquet¹,

Sevin²,

Gaborit³

et al. 2015

ADMET DMPK

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Most identified drug transporters belong to the ATP-binding Cassette (ABC) and Solute Carrier (SLC) families. Recent research indicates that some of these transporters play an important role in the absorption, distribution and excretion of drugs, and are involved in clinically relevant drug-drug interactions for systemic drugs. However, very little is known about the role of drug transporters in human skin in the disposition of topically applied drugs and their involvement in drug-drug interactions. The aim of this work was to compare the expression in human skin (vs human hepatocytes and kidney) of SLC transporters included in the EMA guidance as the most likely clinical sources of drug interactions. The expression of SLC transporters in human tissues was analyzed by quantitative RT-PCR. Modulation of SLC47A1 and SLC47A2 (MATE1 and MATE2) expression was analyzed after treatment of human skin in organ-culture with rifampicin and UV irradiation. The expression of SLCO2B1 (OATPB), SLCO3A1 (OATPD), SLCO4A1 (OATPE), SLC47A1 and SLC47A2 (MATE1 and MATE2)

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“…In addition, another study reported that PXRs have anti-inflammation functions via suppression of signal transduction pathways (Sun et al, 2015). Although we did not observe the binding of PXR to the clotrimazole-responsive element, the increase in clotrimazole-induced MRP3 reporter activity was suppressed by PXR overexpression (Fig.…”

Section: Discussionmentioning

confidence: 48%

Activation of p38 Mitogen-Activated Protein Kinase by Clotrimazole Induces Multidrug Resistance-Associated Protein 3 Activation through a Novel Transcriptional Element

Sasaki

Inami

Numata

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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Multidrug resistance-associated protein 3 (MRP3) is a basolaterally localized transporter in the liver and contributes to the transport of various metabolites such as conjugates of endogenous compounds and drugs from hepatocytes. MRP3 expression in the human liver is low under normal physiologic conditions but is induced by drug treatment. Although several studies have identified a region necessary for the basal transcription of MRP3, no region that responds to drugs has been reported. To identify the xenobiotic-responsive elements of MRP3, we constructed a luciferase reporter plasmid containing the MRP3 59-flanking region up to 210 kb upstream from the transcription start site. Among typical nuclear receptor ligands, clotrimazole dramatically enhanced MRP3 reporter activity in HepG2 cells, whereas rifampicin had no effect. We then conducted MRP3 reporter assays with deletion or mutation constructs to identify a clotrimazole-responsive element. The element was located approximately 26.8 kb upstream from the MRP3 transcription start site. Overexpression of the pregnane X receptor did not enhance clotrimazole-mediated transcription. We found that clotrimazole was toxic to HepG2 cells and we therefore investigated whether mitogen-activated protein kinase (MAPK) activation is involved in the transactivation of MRP3 by clotrimazole. p38 MAPK inhibitor SB203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole] suppressed MRP3 mRNA expression induced by clotrimazole, whereas c-Jun N-terminal kinase inhibitor SP600125 (1,9-pyrazoloanthrone) and extracellular signal-regulated kinase inhibitor PD98059 [2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one] did not. Phosphorylated p38 MAPK was detected in HepG2 cells treated with clotrimazole. These results suggest that activation of the p38 MAPK pathway induces the transcriptional activation of MRP3.

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Pregnane X Receptor Modulates the Inflammatory Response in Primary Cultures of Hepatocytes

Cited by 50 publications

References 55 publications

SUMOylation and Ubiquitylation Circuitry Controls Pregnane X Receptor Biology in Hepatocytes

SUMOylation and Ubiquitylation Circuitry Controls Pregnane X Receptor Biology in Hepatocytes

Characterization of SLC transporters in human skin

Activation of p38 Mitogen-Activated Protein Kinase by Clotrimazole Induces Multidrug Resistance-Associated Protein 3 Activation through a Novel Transcriptional Element

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