Tumor necrosis factor increases mitochondrial oxidant production and induces expression of uncoupling protein-2 in the regenerating rat liver

The growth-stimulatory actions of tumor necrosis factor alpha (TNF-alpha) a fter partial hepatectomy (PH) are difficult to reconcile with its well-esta blished role in the genesis of liver injury. The lethal actions of TNF are thought to involve the induction of oxidant production by mitochondria, It is not known if TNF initiates mitochondrial oxidant production after PH. Fu rthermore, if this potentially toxic response follows PH, it is not clear h ow hepatocytes defend themselves sufficiently so that replication, rather t han death, occurs. These studies test the hypothesis that TNF does increase mitochondrial oxidant production after PH but that these oxidants primaril y promote the induction of antioxidant defenses in regenerating hepatocytes , Consistent with this concept, H2O2 production by liver mitochondria incre ases from 5 minutes to 3 hours after PH, beginning before the transient ind uctions of hepatic NF kB activity (which peaks at 30 minutes post-PH) and u ncoupling protein-2 (UCP-2) (which begins around 30 minutes and peaks from 6-24 hours post-PH). Pretreatment with neutralizing anti-TNF antibodies, wh ich inhibits hepatocyte DNA synthesis after PH, also reduces post-PH hepati c mitochondrial oxidant production by 80% and inhibits NF kappa B activatio n and UCP-2 induction by 50% and 80%, respectively. In contrast, pretreatme nt with D609, an agent that inhibits phosphatidylcholine-specific phospholi pase C, neither inhibits regenerative induction of mitochondrial oxidant pr oduction, UCP-2 expression, nor hepatocyte DNA synthesis, although it inhib its NF kappa B activation by 50%, Given published evidence that NF kappa B is antiapoptotic and that UCP-2 may decrease mitochondrial oxidant producti on in some cells, these results suggest that TNF-dependent increases in oxi dant production by liver mitochondria promote the induction of antioxidant defenses in the regenerating liver.