ANALYSIS OF LIVER-REGENERATION IN MICE LACKING TYPE-1 OR TYPE-2 TUMOR-NECROSIS-FACTOR RECEPTOR - REQUIREMENT FOR TYPE-1 BUT NOT TYPE-2 RECEPTOR

We used KO mice lacking either TNF receptor 1 (TNFR-1) or receptor 2 ( TNFR-2) to determine whether signaling at the start of liver regenerat ion after partial hepatectomy (PH) involves only one or both TNF recep tors and to analyze in more detail the abnormalities caused by lack of TNFR-1 receptor, which is required for the initiation of liver regene ration, Lack of TNFR-2 had little effect on NF-kappa B and STAT3 bindi ng, and no effect in interleukin-6 production after PH, but caused a d elay in AP-1 and C/EBP binding and in the expression of c-jun and c-my c messenger RNA (mRNA), In contrast to mice lacking TNFR-1, which had deficient hepatocyte DNA synthesis and massive lipid accumulation in h epatocytes, TNFR-2 KO mice had normal liver structure and similar leve ls of hepatocyte DNA replication as those of wild type mice. We conclu de that TNFR-1, but not TNFR-2, is necessary for liver regeneration, a nd that NF-kappa B and STAT3 binding are activated by signals transduc ed by TNFR-1, Inhibition of AP-1 and C/EBP binding and in the expressi on of c-jun and c-myc mRNA in the first 4 hours after PH, as well as t he apparent lack of Fos in AP-1 complexes, had no effect on the timing or extent of DNA replication.