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Role of the Toll‐like receptor adaptor protein, TIRAP in regulation of gene expression of hepatic drug metabolizing enzymes
Author(s) -
Ghose Romi,
Guo Tao
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.752.1
Subject(s) - tlr2 , pregnane x receptor , gene expression , microbiology and biotechnology , proinflammatory cytokine , toll like receptor , messenger rna , receptor , gene , chemistry , inflammation , tlr4 , biology , transcription factor , innate immune system , biochemistry , nuclear receptor , immunology
Background Altered expression of drug metabolizing enzymes (DMEs) in inflammation can affect the metabolism and toxicity of drugs. We have recently shown that the Toll‐like receptor (TLR) 2 ligand, lipoteichoic acid (LTA) can regulate the gene expression of drug metabolizing enzymes (DMEs). However, the role of the TLR2 adaptor protein, TIRAP in regulating hepatic DME genes is not known. We hypothesize that TIRAP mediates TLR2‐dependent regulation of hepatic DME gene expression. Methods TIRAP +/+ and TIRAP −/− mice were i.p. injected with LTA, (6mg/kg) or saline. Livers were harvested and RNA and proteins were analyzed by real‐time PCR and western blotting, respectively. Results Cyp2b10, Cyp2a4 and Sultn were significantly reduced by LTA in TIRAP +/+ mice (~70‐80% reduction), but not in TIRAP −/− mice. Gene expression of the DMEs is regulated by members of the nuclear receptor superfamily (PXR, CAR and RXRα). RNA levels of PXR and CAR was significantly reduced by LTA treatment in TIRAP +/+ , but not in TIRAP −/− mice. Interestingly, RNA levels of the pro‐inflammatory cytokines, IL‐1β, IL6 and TNFα were induced by LTA in both the TIRAP +/+ and TIRAP −/− mice. Conclusions TIRAP is involved in regulating hepatic DME gene expression by LTA, but is not involved in regulating LTA‐mediated induction of pro‐inflammatory cytokines in the liver.