Skip to main content
Journal cover image

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

Publication ,  Journal Article
Lee, FY; Li, Y; Zhu, H; Yang, S; Lin, HZ; Trush, M; Diehl, AM
Published in: Hepatology
March 1999

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.

Duke Scholars

Published In

Hepatology

DOI

ISSN

0270-9139

Publication Date

March 1999

Volume

29

Issue

3

Start / End Page

677 / 687

Location

United States

Related Subject Headings

  • Uncoupling Protein 2
  • Tumor Necrosis Factor-alpha
  • Thiones
  • Thiocarbamates
  • Proteins
  • Phosphodiesterase Inhibitors
  • Oxidants
  • Norbornanes
  • Necrosis
  • Mitochondrial Proteins
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Lee, F. Y., Li, Y., Zhu, H., Yang, S., Lin, H. Z., Trush, M., & Diehl, A. M. (1999). Tumor necrosis factor increases mitochondrial oxidant production and induces expression of uncoupling protein-2 in the regenerating mice [correction of rat] liver. Hepatology, 29(3), 677–687. https://doi.org/10.1002/hep.510290320
Lee, F. Y., Y. Li, H. Zhu, S. Yang, H. Z. Lin, M. Trush, and A. M. Diehl. “Tumor necrosis factor increases mitochondrial oxidant production and induces expression of uncoupling protein-2 in the regenerating mice [correction of rat] liver.Hepatology 29, no. 3 (March 1999): 677–87. https://doi.org/10.1002/hep.510290320.
Lee, F. Y., et al. “Tumor necrosis factor increases mitochondrial oxidant production and induces expression of uncoupling protein-2 in the regenerating mice [correction of rat] liver.Hepatology, vol. 29, no. 3, Mar. 1999, pp. 677–87. Pubmed, doi:10.1002/hep.510290320.
Journal cover image

Published In

Hepatology

DOI

ISSN

0270-9139

Publication Date

March 1999

Volume

29

Issue

3

Start / End Page

677 / 687

Location

United States

Related Subject Headings

  • Uncoupling Protein 2
  • Tumor Necrosis Factor-alpha
  • Thiones
  • Thiocarbamates
  • Proteins
  • Phosphodiesterase Inhibitors
  • Oxidants
  • Norbornanes
  • Necrosis
  • Mitochondrial Proteins