Details

Autor(en) / Beteiligte

• Shah, P.
• Omoluabi, O.
• Moorthy, B.
• Ghose, R.

Titel

Role of Adaptor Protein Toll-Like Interleukin Domain Containing Adaptor Inducing Interferon   in Toll-Like Receptor 3- and 4-Mediated Regulation of Hepatic Drug Metabolizing Enzyme and Transporter Genes

Ist Teil von

• Drug metabolism and disposition, 2016-01, Vol.44 (1), p.61-67

Erscheinungsjahr

2016

Quelle

EZB Free E-Journals

Beschreibungen/Notizen

• 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)-[beta] (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 super(+/+) and TRIF super(-/-) 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 super(+/+) mice. This downregulation was not attenuated in TRIF super(-/-) mice. Induction of cytokines by LPS was observed in both TRIF super(+/+) and TRIF super(-/-) mice. Cytokine induction was delayed in polyI:C-treated TRIF super(-/-) 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.