Differential Role of Toll-Interleukin 1 Receptor Domain-Containing Adaptor Protein in Toll-Like Receptor 2-Mediated Regulation of Gene Expression of Hepatic Cytokines and Drug-Metabolizing Enzymes

Ghose, Romi; Guo, Tao; Vallejo, Jesús G.; Gandhi, Adarsh

doi:10.1124/dmd.110.037382

Cited by 32 publications

(34 citation statements)

References 38 publications

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“…These cytokines act on hepatocytes to reduce the expression of DME/transporter genes (Renton, 2004;Aitken et al, 2006). We have also shown that activation of TLR2 by lipoteichoic acid (LTA) (Gram-positive bacterial component) downregulates the expression of select DME and transporter genes (Ghose et al, 2009(Ghose et al, , 2011.…”

Section: Introductionmentioning

confidence: 89%

“…The sequences of the primers and probes were obtained from the literature, as reported previously (Ghose et al, 2004(Ghose et al, , 2009(Ghose et al, , 2011. All oligonucleotides were purchased from Sigma Genosys (Houston, TX), and all real-time polymerase chain reaction (PCR) reagents were purchased from Applied Biosystems (Foster City, CA).…”

Section: Methodsmentioning

confidence: 99%

“…Primary mouse hepatocytes were isolated from CAR +/+ and CAR 2/2 mice using the two-step collagenase perfusion technique, as described previously (Li et al, 2002;Ghose et al, 2011). In short, after digestion, the liver was excised and then the hepatocytes were purified using a Percoll gradient (33%), washed, and screened for viability using trypan blue exclusion technique.…”

Section: Methodsmentioning

confidence: 99%

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Role of Constitutive Androstane Receptor in Toll-Like Receptor-Mediated Regulation of Gene Expression of Hepatic Drug-Metabolizing Enzymes and Transporters

et al. 2013

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Impairment of drug disposition in the liver during inflammation has been attributed to downregulation of gene expression of drugmetabolizing enzymes (DMEs) and drug transporters. Inflammatory responses in the liver are primarily mediated by Toll-like receptors (TLRs). We have recently shown that activation of TLR2 or TLR4 by lipoteichoic acid (LTA) and lipopolysaccharide (LPS), respectively, leads to the downregulation of gene expression of DMEs/transporters. However, the molecular mechanism underlying this downregulation is not fully understood. The xenobiotic nuclear receptors, pregnane X receptor (PXR) and constitutive androstane receptor (CAR), regulate the expression of DMEs/transporter genes. Downregulation of DMEs/transporters by LTA or LPS was associated with reduced expression of PXR and CAR genes. To determine the role of CAR, we injected CAR +/+ and CAR 2/2 mice with LTA or LPS, which significantly downregulated (∼40%-60%) RNA levels of the DMEs, cytochrome P450 (Cyp)3a11, Cyp2a4, Cyp2b10, uridine diphosphate glucuronosyltransferase 1a1, amine N-sulfotransferase, and the transporter, multidrug resistance-associated protein 2, in CAR +/+ mice. Suppression of most of these genes was attenuated in LTA-treated CAR 2/2 mice. In contrast, LPS-mediated downregulation of these genes was not attenuated in CAR 2/2 mice.Induction of these genes by mouse CAR activator 1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene was sustained in LTA-but not in LPStreated mice. Similar observations were obtained in humanized CAR mice. We have replicated these results in primary hepatocytes as well. Thus, LPS can downregulate DME/transporter genes in the absence of CAR, whereas the effect of LTA on these genes is attenuated in the absence of CAR, indicating the potential involvement of CAR in LTA-mediated downregulation of DME/ transporter genes.

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Section: Introductionmentioning

confidence: 89%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Role of Constitutive Androstane Receptor in Toll-Like Receptor-Mediated Regulation of Gene Expression of Hepatic Drug-Metabolizing Enzymes and Transporters

et al. 2013

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“…The mechanisms behind this P450 regulation have been investigated, and the nuclear factor k-light-chain-enhancer of activated B cells-dependent inflammatory response and associated relocalization and dimerization of nuclear receptors such as retinoid X receptor, liver X receptor, farnesoid X receptor, constitutive androstane receptor, pregnane X receptor (PXR), and peroxisome proliferator-activated receptor have been implicated (Jover et al, 2002, Yang et al, 2010Ghose et al, 2011). However, P450-specific transcriptional regulation has not been fully characterized, and the question of common pathways versus specific receptor-dependent intracellular signaling pathways is still to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

HepaRG Cells as Human-Relevant In Vitro Model to Study the Effects of Inflammatory Stimuli on Cytochrome P450 Isoenzymes

Rubin¹,

Janefeldt²,

Andersson³

et al. 2014

Drug Metab Dispos

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“…Additionally, Kupffer cells can release cytokines such as tumor necrosis factor a (TNF-a) and interleukin-6 (IL-6) which modulate suppression of CYP3A4 in hepatocytes in vitro (Hoebe et al, 2001;Sunman et al, 2004). Therapeutic proteins that are cytokines or cytokine modulators can suppress DME by acting directly on hepatocytes (Ghose et al, 2011) and/or Kupffer cells, as has been shown for interferon-a-2B (IFNa-2B) with theophylline and methadone clearance (Iafolla, 2002), whereas other therapeutic proteins, such as OKT3 antibody, cause systemic reaction by stimulating cytokine release from PBMCs (Abramowicz et al, 1989;Chatenoud et al, 1990;Herbelin et al, 1999;Wolf et al, 2012). The effects of therapeutic proteins that directly suppress drug metabolism can be examined in a traditional hepatocyte culture (Kraynov et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Anti-CD28 Monoclonal Antibody–Stimulated Cytokines Released from Blood Suppress CYP1A2, CYP2B6, and CYP3A4 in Human Hepatocytes In Vitro

et al. 2014

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Like most infections and certain inflammatory diseases, some therapeutic proteins cause a cytokine-mediated suppression of hepatic drug-metabolizing enzymes, which may lead to pharmacokinetic interactions with small-molecule drugs. We propose a new in vitro method to evaluate the whole blood-mediated effects of therapeutic proteins on drug-metabolizing enzymes in human hepatocytes cocultured with Kupffer cells. The traditional method involves treating hepatocyte cocultures with the therapeutic protein, which detects hepatocyte-and macrophage-mediated suppression of cytochrome P450 (P450). The new method involves treating whole human blood with a therapeutic protein to stimulate the release of cytokines from peripheral blood mononuclear cells (PBMCs), after which plasma is prepared and added to the hepatocyte coculture to evaluate P450 enzyme expression. In this study, human blood was treated for 24 hours at 37°C with bacterial lipopolysaccharide (LPS) or ANC28.1, an antibody against human T-cell receptor CD28. Cytokines were measured in plasma by sandwich immunoassay with electrochemiluminescense detection. Treatment of human hepatocyte cocultures with LPS or with plasma from LPS-treated blood markedly reduced the expression of CYP1A2, CYP2B6, and CYP3A4. However, treatment of hepatocyte cocultures with ANC28.1 did not suppress P450 expression, but treatment with plasma from ANC28.1-treated blood suppressed CYP1A2, CYP2B6, and CYP3A4 activity and mRNA levels. The results demonstrated that applying plasma from human blood treated with a therapeutic protein to hepatocytes cocultured with Kupffer cells is a suitable method to identify those therapeutic proteins that suppress P450 expression by an indirect mechanism-namely, the release of cytokines from PBMCs.

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Differential Role of Toll-Interleukin 1 Receptor Domain-Containing Adaptor Protein in Toll-Like Receptor 2-Mediated Regulation of Gene Expression of Hepatic Cytokines and Drug-Metabolizing Enzymes

Cited by 32 publications

References 38 publications

Role of Constitutive Androstane Receptor in Toll-Like Receptor-Mediated Regulation of Gene Expression of Hepatic Drug-Metabolizing Enzymes and Transporters

Role of Constitutive Androstane Receptor in Toll-Like Receptor-Mediated Regulation of Gene Expression of Hepatic Drug-Metabolizing Enzymes and Transporters

HepaRG Cells as Human-Relevant In Vitro Model to Study the Effects of Inflammatory Stimuli on Cytochrome P450 Isoenzymes

Anti-CD28 Monoclonal Antibody–Stimulated Cytokines Released from Blood Suppress CYP1A2, CYP2B6, and CYP3A4 in Human Hepatocytes In Vitro

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