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 α (RXRα)]. 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 ∼60 to 70% by LPS in wild-type but not in the TLR4-mutant mice. The nuclear protein levels of RXRα were reduced by LPS in wild-type but not in TLR4-mutant mice. Induction of hepatic cytokines (interleukin-1β, tumor necrosis factor-α, and interleukin-6), c-Jun N-terminal kinase, and nuclear factor-κB 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.
Footnotes
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This work was supported by grants from the National Institutes of Health (K01DK076057-02 to R.G. and R01DK56239 to S.J.K.) and by U.S. Public Health Service Grant DK56338, which funds the Texas Medical Center Digestive Diseases Center.
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Portions of this work were in Regulation of Drug Metabolizing Enzymes in Inflammation: Role of the Toll-Like Receptor 4 Signaling Pathway (R. Ghose, D. White, J. Vallejo, and S. J. Karpen), which was presented at Experimental Biology 2007 in Washington, DC, April 28–May 2, 2007.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.107.018051.
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ABBREVIATIONS: DME, drug-metabolizing enzyme; NR, nuclear receptor; PXR, pregnane X receptor; CAR, constitutive androstane receptor; RXR, retinoid X receptor; LPS, lipopolysaccharide; IL, interleukin; TNFα, tumor necrosis factor-α; AP-1, activator protein-1; NF-κB, nuclear factor-κB; JNK, c-Jun N-terminal kinase; TLR, Toll-like receptor; TIRAP, Toll-interleukin 1 receptor domain-containing adaptor protein; IκB, inhibitor of nuclear factor-κB; PCR, polymerase chain reaction; wt, wild-type; P-JNK, phosphorylated JNK.
- Received August 6, 2007.
- Accepted October 9, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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