TUMOR-NECROSIS-FACTOR-ALPHA INDUCES C-JUN DURING THE REGENERATIVE RESPONSE TO LIVER-INJURY

After liver injury, remaining hepatocytes proliferate to regenerate th e liver. Although the precise mechanisms that initiate and localize re generation are unknown, local induction of c-jun is a critical, early step in the response. Treatment of rats with antibodies to tumor necro sis factor-alpha (TNF-alpha), a mediator of liver injury, inhibits reg enerative induction of jun nuclear kinase activity and nuclear c-jun e xpression and alters the DNA binding activity of the c-jun transcripti on factor, AP-1, in liver. Pretreatment with anti-TNF antibodies does not affect pulmonary or renal c-jun expression or AP-1 binding activit y post-partial hepatectomy. In primary hepatocyte cultures, TNF-alpha directly promotes the proliferative actions of mitogens, supporting in vivo evidence that it sensitizes hepatocytes to mitogens. Thus local release of TNF may act in a paracrine fashion to initiate regeneration in the injured liver by promoting induction of critical growth-relate d genes, such as c-jun.