Initiation of liver growth by tumor necrosis factor: deficient liver regeneration in mice lacking type I tumor necrosis factor receptor.
The mechanisms that initiate liver regeneration after resection of liver tissue are not known. To determine whether cytokines are involved in the initiation of liver growth, we studied the regeneration of the liver after partial hepatectomy (PH) in mice lacking type I tumor necrosis factor receptor (TNFR-I). DNA synthesis after PH was severely impaired in these animals, and the expected increases in the binding of the NF-kappaB and STAT3 transcription factors shortly after PH failed to occur. Binding of AP-1 after PH was decreased in TNFR-I knockout mice compared with animals with the intact receptor whereas C/EBP binding was not modified. Injection of interleukin 6 in TNFR-I-deficient animals 30 min before PH corrected the defect in DNA synthesis and restored STAT3 and AP-1 binding to normal levels but had no effect on NF-kappaB binding in the regenerating liver. The results indicate that TNF, signaling through the TNFR-I, can initiate liver regeneration and acts by activating an interleukin 6-dependent pathway that involves the STAT3 transcription factor.
Yamada
Y
Y
Department of Pathology, University of Washington, Seattle 98195, USA.
Kirillova
I
I
Peschon
J J
JJ
Fausto
N
N
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D022762:CCAAT-Enhancer-Binding Proteins; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000378:metabolism; D006498:Hepatectomy; D015850:Interleukin-6 / Q000235:genetics / Q000494:pharmacology; D008115:Liver Regeneration / Q000187:drug effects / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D009929:Organ Size; D011485:Protein Binding; D012333:RNA, Messenger / Q000096:biosynthesis; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism
D015703:Antigens, CD; D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D016328:NF-kappa B; D009687:Nuclear Proteins; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D018808:Transcription Factor AP-1