Disruption of TAK1 in hepatocytes causes hepatic injury, inflammation, fibrosis, and carcinogenesis.
TGF-beta-activated kinase 1 (TAK1) is a MAP3K family member that activates NF-kappaB and JNK via Toll-like receptors and the receptors for IL-1, TNF-alpha, and TGF-beta. Because the TAK1 downstream molecules NF-kappaB and JNK have opposite effects on cell death and carcinogenesis, the role of TAK1 in the liver is unpredictable. To address this issue, we generated hepatocyte-specific Tak1-deficient (Tak1DeltaHEP) mice. The Tak1DeltaHEP mice displayed spontaneous hepatocyte death, compensatory proliferation, inflammatory cell infiltration, and perisinusoidal fibrosis at age 1 month. Older Tak1DeltaHEP mice developed multiple cancer nodules characterized by increased expression of fetal liver genes including alpha-fetoprotein. Cultures of primary hepatocytes deficient in Tak1 exhibited spontaneous cell death that was further increased in response to TNF-alpha. TNF-alpha increased caspase-3 activity but activated neither NF-kappaB nor JNK in Tak1-deficient hepatocytes. Genetic abrogation of TNF receptor type I (TNFRI) in Tak1DeltaHEP mice reduced liver damage, inflammation, and fibrosis compared with unmodified Tak1DeltaHEP mice. In conclusion, hepatocyte-specific deletion of TAK1 in mice resulted in spontaneous hepatocyte death, inflammation, fibrosis, and carcinogenesis that was partially mediated by TNFR signaling, indicating that TAK1 is an essential component for cellular homeostasis in the liver.
Inokuchi
Sayaka
S
Department of Medicine, School of Medicine, University of California San Diego, La Jolla, CA 92093-0702, USA.
Aoyama
Tomonori
T
Miura
Kouichi
K
Osterreicher
Christoph H
CH
Kodama
Yuzo
Y
Miyai
Katsumi
K
Akira
Shizuo
S
Brenner
David A
DA
Seki
Ekihiro
E
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics*; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017209:Apoptosis; D002455:Cell Division / Q000502:physiology; D005260:Female; D017353:Gene Deletion; D022781:Hepatocytes / Q000473:pathology / Q000502:physiology; D007249:Inflammation / Q000473:pathology*; D008099:Liver / Q000473:pathology*; D008103:Liver Cirrhosis / Q000473:pathology*; D008113:Liver Neoplasms / Q000473:pathology*; D008115:Liver Regeneration / Q000235:genetics; D008297:Male; D051379:Mice; D012727:Sex Characteristics
D048868:Adaptor Proteins, Signal Transducing; C498761:Tab2 protein, mouse; D000410:Alanine Transaminase