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

Published

Journal Article

The growth-stimulatory actions of tumor necrosis factor alpha (TNF-alpha) 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 kB 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 kappaB 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 kappaB activation by 50%. Given published evidence that NF kappaB 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.

Full Text

Duke Authors

Cited Authors

  • Lee, FY; Li, Y; Zhu, H; Yang, S; Lin, HZ; Trush, M; Diehl, AM

Published Date

  • March 1999

Published In

Volume / Issue

  • 29 / 3

Start / End Page

  • 677 - 687

PubMed ID

  • 10051468

Pubmed Central ID

  • 10051468

International Standard Serial Number (ISSN)

  • 0270-9139

Digital Object Identifier (DOI)

  • 10.1002/hep.510290320

Language

  • eng

Conference Location

  • United States