Induction of Early-immediate Genes by Tumor Necrosis Factor Alpha Contribute to Liver Repair Following Chemical-induced Hepatotoxicity

We and others have shown that tumor necrosis factor alpha (TNF-alpha) expression is increased in the livers of experimental animals following exposure to the chemical hepatotoxin, carbon tetrachloride (CCl4). Because TNF-alpha is involved in mediating inflammatory responses, its elevated expression is presumed to be associated with potentiating hepatotoxicity and/or aiding in liver repair processes. To study the role of TNF-alpha in chemical-induced hepatotoxicity, mice were administered neutralizing antibodies to TNF-alpha before administration of low, but hepatotoxic, doses of CCl4. Antibody treatment prevented CCl4-mediated increases in early-immediate gene expression associated with liver regeneration, including expression of c-jun and c-fos proto-oncogenes, as well as DNA binding of the activator protein-1 (AP-1) nuclear transcription factor. Hepatocyte proliferation following CCl4 treatment was also reduced in anti-TNF-alpha antibody-treated mice, as evidenced by a lack of proliferating cell nuclear antigen (PCNA) staining. Antibody treatment slightly delayed liver repair processes, as evidenced by extending the period in which plasma liver enzyme levels were increased and hepatocellular necrosis could be observed. Consistent with the above observations, injection of recombinant TNF-alpha into control mice induced rapid expression of c-jun and c-fos proto-oncogenes. Taken together, these results indicate that TNF-alpha positively modulates liver recovery following CCl4 exposure presumably by stimulating early-immediate genes involved in hepatic mitogenesis, a phenomenon also observed following partial hepatectomy.