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- 학술저널
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- 2017.1
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Mice deficient in the toll-like receptor (TLR) or the myeloid differentiation factor 88 (MyD88) are resistant to acute liver failure (ALF) with sudden death of hepatocytes. Chalcone derivatives from medicinal plants protect from hepatic damages including ALF, but their mechanisms remain to be clarified. Here, we focused on molecular basis of piperidylmethyloxychalcone (PMOC) in the treatment of TLR/MyD88-associated ALF. C57BL/6J mice were sensitized with D-galactosamine (GalN) and challenged with Escherichia coli lipopolysaccharide (LPS, TLR4 agonist) or oligodeoxynucleotide containing unmethylated CpG motif (CpG ODN, TLR9 agonist) for induction of ALF. Post treatment with PMOC sequentially ameliorated hepatic inflammation, apoptosis of hepatocytes, severe liver injury and shock-mediated death in ALF-induced mice. As a mechanism, PMOC inhibited the catalytic activity of TGF-β-activated kinase 1 (TAK1) in a competitive manner with respect to ATP, displaced fluorescent ATP probe from the complex with TAK1, and docked at the ATP-binding active site on the crystal structure of TAK1. Moreover, PMOC inhibited TAK1 auto-phosphorylation, which is an axis in the activating pathways of nuclear factor-κB (NF-κB) or activating protein 1 (AP1), in the liver with ALF in vivo or in primary liver cells stimulated with TLR agonists in vitro. PMOC consequently suppressed TAK1-inducible NF-κB or AP1 activity in the inflammatory injury, an early pathogenesis leading to ALF. The results suggested that PMOC could contribute to the treatment of TLR/MyD88-associated ALF with the ATP-binding site of TAK1 as a potential therapeutic target.
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참고문헌 (25)
참고문헌 신청
Ajibade AA / 2013 / Cell type-specific function of TAK1 in innate immune signaling / Trends Immunol 34 : 307 ~ 316
Baer M / 1998 / Tumor necrosis factor α transcription in macrophages is attenuated by an autocrine factor that preferentially induces NF-κB p50 / Mol Cell Biol 18 : 5678 ~
Bantel H / 2012 / Mechanisms of cell death in acute liver failure / Front Physiol 3 : 79 ~
Bauer S / 2013 / Toll-like receptor 9 processing : the key event in Toll-like receptor 9 activation? / Immunol Lett 149 : 85 ~ 87
Bryant CE / 2015 / Toll-like receptor signalling through macromolecular protein complexes / Mol Immunol 63 : 162 ~ 165
Baer M / 1998 / Tumor necrosis factor α transcription in macrophages is attenuated by an autocrine factor that preferentially induces NF-κB p50 / Mol Cell Biol 18 : 5678 ~
Bantel H / 2012 / Mechanisms of cell death in acute liver failure / Front Physiol 3 : 79 ~
Bauer S / 2013 / Toll-like receptor 9 processing : the key event in Toll-like receptor 9 activation? / Immunol Lett 149 : 85 ~ 87
Bryant CE / 2015 / Toll-like receptor signalling through macromolecular protein complexes / Mol Immunol 63 : 162 ~ 165
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