Interleukin-1 Controls the Constitutive Expression of the Cyp7a1 Gene by Regulating the Expression of Cyp7a1 Transcriptional Regulators in the Mouse Liver

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    • Iwakura Yoichiro
    • Center for Experimental Medicine and Systems Biology, Institute of Medical Science, The University of Tokyo|Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency
    • Degawa Masakuni
    • Department of Molecular Toxicology and Global COE Program, School of Pharmaceutical Sciences, University of Shizuoka


Our previous study using interleukin-1α/β-knockout (IL-1-KO) and wild-type (WT) mice demonstrated that IL-1 acts as a positive factor for constitutive gene expression of hepatic cytochrome P4507a1 (Cyp7a1). In this study, to clarify the role of IL-1 in the expression of the hepatic <i>Cyp7a1</i> gene, we focused on <i>Cyp7a1</i> transcriptional regulators such as α-fetoprotein transcription factor (FTF), liver X receptor α (LXRα), hepatocyte nuclear factor 4α (HNF4α) and small heterodimer partner (SHP) and examined the effects of IL-1 on their gene expression by real-time reverse-transcription polymerase chain reaction using IL-1-KO and WT mice. We observed no significant differences between sex-matched IL-1-KO and WT mice with regard to gene expression levels of FTF, LXRα, and HNF4α, all of which are positive transcriptional regulators for the <i>Cyp7a1</i> gene. However, interindividual differences in hepatic FTF and LXRα expression were closely dependent on the gene expression level(s) of hepatic IL-1 and tumor necrosis factor-α (TNF-α), while interindividual differences in hepatic HNF4α were clearly correlated with the expression of IL-1, but not TNF-α. In contrast, the gene expression level of SHP, which is a negative transcriptional regulator of the <i>Cyp7a1</i> gene through inhibition of FTF function, was higher in IL-1-KO mice than in sex-matched WT mice. These findings demonstrate that, like TNF-α, IL-1 positively controls the gene expression of <i>Cyp7a1</i> transcriptional upregulators but, in contrast to the previously reported action of TNF-α, IL-1 also acts to downregulate SHP gene expression.


  • Biological and Pharmaceutical Bulletin

    Biological and Pharmaceutical Bulletin 34(10), 1644-1647, 2011

    The Pharmaceutical Society of Japan


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