Increased DNA binding activity of NF-kappaB, STAT-3, SMAD3 and AP-1 in acutely damaged liver.

AIM: To investigate the role of genes and kinetics of specific transcription factors in liver regeneration, and to analyze the gene expression and the activity of some molecules crucially involved in hepatic regeneration.

METHODS: USING gel-shift assay and RT-PCR, transcription factors, such as NF-kappaB, STAT-3, SMAD3 and AP-1, and gene expression of inducible nitric oxide synthase (iNOS), hepatocyte growth factor (HGF) and c-met were analyzed in an animal model of chemically induced hepatectomy.

RESULTS: Gene expression of HGF and its receptor c-met peaked at 3 h and 24 h after acute CCl(4) intoxi-cation. iNOS expression was only observed from 6 to 48 h. Transcriptional factor NF-kappaB had an early activation at 30 min after acute liver damage. STAT-3 peaked 3 h post-intoxication, while AP-1 displayed a peak of activation at 48 h. SMAD3 showed a high activity at all analyzed times.

CONCLUSION: TNF-alpha and IL-6 play a central role in hepatic regeneration. These two molecules are responsible for triggering the cascade of events and switch-on of genes involved in cell proliferation, such as growth factors, kinases and cyclins which are direct participants of cell proliferation.