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

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.

Distinct Effects of Inflammation on Cytochrome P450 Regulation and Drug Metabolism: Lessons from Experimental Models and a Potential Role for Pharmacogenetics

“…IL-1β treatment induces JNK expression which can phosphorylate RXR, leading to reduced nuclear binding activity and subsequently inhibited RXR-dependent hepatic gene expression [ 68 ]. Additionally, LPS-induced downregulation of P450 genes was attenuated upon treatment with a specific JNK inhibitor in a primary mouse hepatocyte model [ 69 ]. Thus, JNK can play a role in inflammation-mediated downregulation of nuclear receptors with RXR as partner.…”

Physiological Regulation of Drug Metabolism and Transport: Pregnancy, Microbiome, Inflammation, Infection, and Fasting

“…(Aitken et al, 2006;Morgan, 2017). Stimulation of the innate immune system via Toll-like receptors contributes to some of these changes (Shah et al, 2016), with proinflammatory cytokines such as IL-1b and IL-6, tumor necrosis factor-a, and interferons able to act directly via their respective receptors expressed on hepatocytes to regulate expression of DME genes (Aitken et al, 2006).…”

Regulation of drug-metabolizing enzymes in infectious and inflammatory disease: implications for biologics–small molecule drug interactions

“…Apart from RXRα, JNK also inhibits glucocorticoid receptor activity, leading to suppression of CAR gene expression [68]. Furthermore, LPS mediated down-regulation of DMEs was attenuated when primary mouse hepatocytes were treated with specific JNK inhibitor (SP600125, 10µM) [69]. …”