Abstract
The expression and activity of hepatic drug metabolizing enzymes and transporters (DMETs) is altered during infection and inflammation. Inflammatory responses in the liver are primarily mediated 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, while TRIF is the only adaptor protein involved in the TLR3 pathway. We have shown previously that LPS-mediated down-regulation of DMETs is independent of TIRAP. To determine the role of TRIF, we treated TRIF+/+ and TRIF-/- mice with LPS or polyI:C. LPS down-regulated (~40-60%) Cyp3a11, Cyp2a4, Ugt1a1, Mrp2 mRNA levels, whereas polyI:C down-regulated (~30-60%) Cyp3a11, Cyp2a4, Cyp1a2, Cyp2b10, Ugt1a1, Mrp2, Mrp3 mRNA levels in TRIF+/+ mice. This down-regulation 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 pre-treated 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 down-regulation of DMETs through TLR4 & 3. JNK-dependent mechanisms likely mediate this down-regulation.
- The American Society for Pharmacology and Experimental Therapeutics