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 liv er tissue are not known, To determine whether cytokines are involved i n the initiation of liver growth, we studied the regeneration of the l iver after partial hepatectomy (PH) in mice lacking type I tumor necro sis factor receptor (TNFR-I), DNA synthesis after PH was severely impa ired in these animals, and the expected increases in the binding of th e NF-kappa B and STAT3 transcription factors shortly after PH failed t o occur, Binding of AP-1 after PH was decreased in TNFR-I knockout mic e compared with animals with the intact receptor whereas C/EBP binding was not modified, Injection of interleukin 6 in TNFR-I-deficient anim als 30 min before PH corrected the defect in DNA synthesis and restore d STAT3 and AP-1 binding to normal Levels but had no effect on NF-kapp a B 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 ST AT3 transcription factor.