Differential role of Toll-interleukin 1 receptor domain-containing adaptor protein in Toll-like receptor 2-mediated regulation of gene expression of hepatic cytokines and drug-metabolizing enzymes

Drug Metab Dispos. 2011 May;39(5):874-81. doi: 10.1124/dmd.110.037382. Epub 2011 Feb 8.


Pharmacological activities of drugs are impaired during inflammation because of reduced expression of hepatic drug-metabolizing enzyme genes (DMEs) and their regulatory nuclear receptors (NRs): pregnane X receptor (PXR), constitutive androstane receptor (CAR), and retinoid X receptor (RXRα). We have shown that a component of Gram-positive bacteria, lipoteichoic acid (LTA) induces proinflammatory cytokines and reduces gene expression of hepatic DMEs and NRs. LTA is a Toll-like receptor 2 (TLR2) ligand, which initiates signaling by recruitment of Toll-interleukin 1 receptor domain-containing adaptor protein (TIRAP) to the cytoplasmic TIR domain of TLR2. To determine the role of TIRAP in TLR2-mediated regulation of DME genes, TLR2(+/+), TLR2(-/-), TIRAP(+/+), and TIRAP(-/-) mice were given LTA injections. RNA levels of the DMEs (Cyp3a11, Cyp2b10, and sulfoaminotransferase), xenobiotic NRs (PXR and CAR), and nuclear protein levels of the central NR RXRα were reduced ∼ 50 to 60% in LTA-treated TLR2(+/+) but not in TLR2(-/-) mice. Induction of hepatic cytokines (interleukin-1β, tumor necrosis factor-α, and interleukin-6), c-Jun NH(2)-terminal kinase, and nuclear factor-κΒ was blocked in TLR2(-/-) mice. As expected, expression of hepatic DMEs and NRs was reduced by LTA in TIRAP(+/+) but not in TIRAP(-/-) mice. Of interest, cytokine RNA levels were induced in the livers of both the TIRAP(+/+) and TIRAP(-/-) mice, whereas LTA-mediated induction of serum cytokines was attenuated in TIRAP(-/-) mice. LTA-mediated down-regulation of DME genes was attenuated in hepatocytes from TLR2(-/-) or TIRAP(-/-) mice and in small interfering RNA-treated hepatocytes. Thus, the effect of TLR2 on DME genes in hepatocytes was mediated by TIRAP, whereas TIRAP was not involved in mediating the effects of TLR2 on cytokine expression in the liver.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cells, Cultured
  • Cytochrome P-450 Enzyme System / genetics
  • Cytochrome P-450 Enzyme System / physiology
  • Cytokines / biosynthesis
  • Cytokines / blood
  • Cytokines / genetics
  • Cytokines / metabolism*
  • Down-Regulation
  • Gene Expression
  • Hepatocytes
  • Inactivation, Metabolic / genetics*
  • Inactivation, Metabolic / immunology
  • Inactivation, Metabolic / physiology*
  • Lipopolysaccharides / physiology*
  • Liver / immunology
  • Liver / metabolism
  • Male
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / physiology*
  • Metabolic Detoxication, Phase I / genetics
  • Metabolic Detoxication, Phase I / physiology
  • Metabolic Detoxication, Phase II / genetics
  • Metabolic Detoxication, Phase II / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / physiology*
  • Receptors, Interleukin-1 / genetics
  • Receptors, Interleukin-1 / physiology*
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • Teichoic Acids
  • Toll-Like Receptor 2 / genetics
  • Toll-Like Receptor 2 / physiology*


  • Cytokines
  • Lipopolysaccharides
  • Membrane Glycoproteins
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Interleukin-1
  • TIRAP protein, mouse
  • Teichoic Acids
  • Toll-Like Receptor 2
  • lipoteichoic acid
  • Cytochrome P-450 Enzyme System