Regulation of Hepatic Drug-Metabolizing Enzyme Genes by Toll-Like Receptor 4 Signaling Is Independent of Toll-Interleukin 1 Receptor Domain-Containing Adaptor Protein

Abstract

During inflammation, drug metabolism and clearance are altered due to suppression of hepatic drug-metabolizing enzyme (DME) genes and their regulatory nuclear receptors (NRs) [pregnane X receptor, constitutive androstane receptor, and retinoid X receptor alpha (RXRalpha)]. The bacterial endotoxin, lipopolysaccharide (LPS), induces expression of proinflammatory cytokines in the liver, which contribute to altered DME expression. LPS binds to the cell-surface receptor, Toll-like receptor 4 (TLR4), which initiates a signal transduction cascade, including recruitment of the Toll-interleukin 1 receptor domain-containing adaptor protein (TIRAP). However, the role of TLR4 and TIRAP in LPS-mediated regulation of hepatic DME gene expression is not known. Wild-type (C3HeB/FeJ), TLR4-mutant (C3H/HeJ), TIRAP(+/+), and TIRAP(-/-) mice were injected i.p. with LPs. RNA levels of the major hepatic DME, Cyp3a11 and Ugt1a1, and the NRs were suppressed approximately 60 to 70% by LPS in wild-type but not in the TLR4-mutant mice. The nuclear protein levels of RXRalpha were reduced by LPS in wild-type but not in TLR4-mutant mice. Induction of hepatic cytokines (interleukin-1beta, tumor necrosis factor-alpha, and interleukin-6), c-Jun N-terminal kinase, and nuclear factor-kappaB was blocked in TLR4-mutant mice. Surprisingly, LPS had the same effect on cytokines, kinases, NRs, and DME genes in livers of both TIRAP(+/+) and TIRAP(-/-) mice, indicating that TIRAP is not essential for TLR4-mediated suppression of NRs and DMEs in liver. However, TIRAP(-/-) mice have reduced serum cytokine expression compared with TIRAP(+/+) mice in response to LPS. This shows that although TIRAP mediates inflammatory responses induced by LPS, it is not essential in regulating LPS-mediated alterations of gene expression in liver.