| セッション情報 |
The 2nd JSGE International Topic Conference
1）Inflammation and Hepatocellular Carcinoma
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| タイトル |
IT1-1：TAK1 is a Gatekeeper Protein that Prevents Spontaneous Apoptosis, Inflammation, Fibrosis and Carcinogenesis in the Liver
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| 演者 |
Seki Ekihiro（Division of Gastroenterology, Department of Medicine, University of California, San Diego, School of Medicine, USA） |
| 共同演者 |
Yang Ling（Division of Gastroenterology, Department of Medicine, University of California, San Diego, School of Medicine, USA）, Inokuchi Sayaka（Division of Gastroenterology, Department of Medicine, University of California, San Diego, School of Medicine, USA） |
| 抄録 |
Transforming growth factor β-activated kinase 1（TAK1）is a MAP kinase kinase kinase that regulates activation of NF-κB and JNK pathways in TLRs, IL-1, TNF and TGFβ signaling. NF-κB and JNK are essential for regulating hepatocyte regeneration, cell death and carcinogenesis. However, the role of TAK1 in hepatocytes remains unclear. To investigate the role of TAK1 in the liver, we generated hepatocyte specific TAK1 deleted mice（TAK1ΔHEP mice）by crossing TAK1-flox mice with Albumin-cre transgenic mice. 1-month old-TAK1ΔHEP mice spontaneously developed heatocyte apoptosis, compensatory hepatocyte proliferation, inflammation and liver fibrosis. Primary cultured TAK1-/- hepatocytes were susceptible to TNF-induced cell death. Notably, 9-month old-TAK1ΔHEP mice spontaneously developed hepatocellular carcinoma（HCC）. The importance of TNF receptor（TNFR）signaling was further demonstrated by suppression of liver injury, inflammation, fibrosis and HCC in TNFR/TAK1 double knockout mice. We also found that TLR4, TLR9 and MyD88, but not IL-1R, are crucial for spontaneous induction of liver inflammation, fibrosis and HCC. We then examined the role of TGFβ signaling in TAK1ΔHep mice. HCC in TAK1ΔHep mice showed high levels of TGFβ, TGFβR2 and phospho-smad2/3. Tak1ΔHEP mice had increased hepatocyte death, compensatory hepatocyte proliferation, inflammatory gene expression and fibrosis whereas ablation of Tgfbr2 abolished these phenotypes in TAK1ΔHEP mice. TAK1-/- hepatocytes were susceptible to TGFβ-mediated death and showed increased Smad2/3 phosphorylation. TAK1-/- hepatocytes had decreased TGFβ-mediated p38, JNK and NF-κB activation. Ablation of hepatocyte Smad4 prevented death in Tak1-/- hepatocytes. 9-month-old TAK1/TGFβR2 and TAK1/Smad4 double knockout mice had fewer and smaller HCC than TAK1ΔHEP single knockout mice. In conclusion, the deletion of TAK1 induces liver injury, inflammation, fibrosis and HCC, which are mediated by signaling through TNFR1, TLR4, TLR9 and TGFβ. |
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