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

E. Y. Lee Janet, Yunbo Li, Hong Zhu, Shiqi Yang, Hui Lin Zhi, Michael Trush, Anna Mae Diehl

Research output: Contribution to journalArticlepeer-review

143 Scopus citations

Abstract

The growth-stimulatory actions of tumor necrosis factor α (TNF-α) after partial hepatectomy (PH) are difficult to reconcile with its well- established 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. Furthermore, if this potentially toxic response follows PH, it is not clear how hepatocytes defend themselves sufficiently so that replication, rather than death, occurs. These studies test the hypothesis that TNF does increase mitochondrial oxidant production after PH but that these oxidants primarily promote the induction of antioxidant defenses in regenerating hepatocytes. Consistent with this concept, H2O2 production by liver mitochondria increases from 5 minutes to 3 hours after PH, beginning before the transient inductions of hepatic NF κB activity (which peaks at 30 minutes post-PH) and uncoupling protein-2 (UCP-2) (which begins around 30 minutes and peaks from 6-24 hours post-PH). Pretreatment with neutralizing anti-TNF antibodies, which inhibits hepatocyte DNA synthesis after PH, also reduces post-PH hepatic mitochondrial oxidant production by 80% and inhibits NF κB activation and UCP-2 induction by 50% and 80%, respectively. In contrast, pretreatment with D609, an agent that inhibits phosphatidylcholine-specific phospholipase C, neither inhibits regenerative induction of mitochondrial oxidant production, UCP-2 expression, nor hepatocyte DNA synthesis, although it inhibits NF κB activation by 50%. Given published evidence that NF κB is antiapoptotic and that UCP-2 may decrease mitochondrial oxidant production in some cells, these results suggest that TNF-dependent increases in oxidant production by liver mitochondria promote the induction of antioxidant defenses in the regenerating liver.

Original languageEnglish (US)
Pages (from-to)677-687
Number of pages11
JournalHepatology
Volume29
Issue number3
DOIs
StatePublished - 1999
Externally publishedYes

ASJC Scopus subject areas

  • Hepatology

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