title: Role of Adaptor Protein Toll-Like Interleukin Domain Containing Adaptor Inducing Interferon β in Toll-Like Receptor 3- and 4-Mediated Regulation of Hepatic Drug Metabolizing Enzyme and Transporter Genes.
abstract: The expressions and activities of hepatic drug-metabolizing enzymes and transporters (DMETs) are altered during infection and inflammation. Inflammatory responses in the liver are mediated primarily by Toll-like receptor (TLR)-signaling, which involves recruitment of Toll/interleukin (IL)-1 receptor (TIR) domain containing adaptor protein (TIRAP) and TIR domain containing adaptor inducing interferon (IFN)-β (TRIF) that eventually leads to induction of proinflammatory cytokines and mitogen-activated protein kinases (MAPKs). Lipopolysaccharide (LPS) activates the Gram-negative bacterial receptor TLR4 and polyinosinic:polycytidylic acid (polyI:C) activates the viral receptor TLR3. TLR4 signaling involves TIRAP and TRIF, whereas TRIF is the only adaptor protein involved in the TLR3 pathway. We have shown previously that LPS-mediated downregulation of DMETs is independent of TIRAP. To determine the role of TRIF, we treated TRIF(+/+) and TRIF(-/-) mice with LPS or polyI:C. LPS downregulated (∼40%-60%) Cyp3a11, Cyp2a4, Ugt1a1, Mrp2 mRNA levels, whereas polyI:C downregulated (∼30%-60%) Cyp3a11, Cyp2a4, Cyp1a2, Cyp2b10, Ugt1a1, Mrp2, and Mrp3 mRNA levels in TRIF(+/+) mice. This downregulation was not attenuated in TRIF(-/-) mice. Induction of cytokines by LPS was observed in both TRIF(+/+) and TRIF(-/-) mice. Cytokine induction was delayed in polyI:C-treated TRIF(-/-) mice, indicating that multiple mechanisms mediating polyI:C signaling exist. To assess the role of MAPKs, primary hepatocytes were pretreated with specific inhibitors before treatment with LPS/polyI:C. We found that only the c-jun-N-terminal kinase (JNK) inhibitor attenuated the down-regulation of DMETs. These results show that TRIF-independent pathways can be involved in the downregulation of DMETs through TLR4 and 3. JNK-dependent mechanisms likely mediate this downregulation.
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston (P.S, O.O., R.G.), and Department of Pediatrics, Baylor College of Medicine (B.M.), Houston, Texas.
authors.forename: Pranav
authors.initials: P
authors.lastname: Shah
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston (P.S, O.O., R.G.), and Department of Pediatrics, Baylor College of Medicine (B.M.), Houston, Texas.
authors.forename: Ozozoma
authors.initials: O
authors.lastname: Omoluabi
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston (P.S, O.O., R.G.), and Department of Pediatrics, Baylor College of Medicine (B.M.), Houston, Texas.
authors.forename: Bhagavatula
authors.initials: B
authors.lastname: Moorthy
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston (P.S, O.O., R.G.), and Department of Pediatrics, Baylor College of Medicine (B.M.), Houston, Texas rghose@uh.edu.
authors.forename: Romi
authors.initials: R
authors.lastname: Ghose
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology*; D007527:Isoenzymes; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008810:Mice, Inbred C57BL; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D011070:Poly I-C / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction; D051196:Toll-Like Receptor 3 / Q000819:agonists / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000378:metabolism*; D000099148:UGT1A1 Enzyme
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D003577:Cytochrome P-450 Enzyme System; D016207:Cytokines; D014453:Glucuronosyltransferase; D007527:Isoenzymes; D048031:JNK Mitogen-Activated Protein Kinases; D008070:Lipopolysaccharides; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011070:Poly I-C; D047428:Protein Kinase Inhibitors; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D000099148:UGT1A1 Enzyme; C476286:Ticam1 protein, mouse; C519703:TLR3 protein, mouse; C493487:Tlr4 protein, mouse