Role of tnf-α in dimethylnitrosamine-induced hepatotoxicity

M. S. Rutherford, T. Horn, A. Bhattacharjee, V. Lappi, T. O'Brien, L. B. Schook

Research output: Contribution to journalArticlepeer-review


Récent investigations demonstrate the involvement of tumor necrosis factor-alpha (TNF-α) in hepatocellular disruption associated with xenobiotic exposure. In that the actions of TNF-α are signaled through two distinct receptors (TNFR55 and TNFR75), we have utilized gene knockout mice deficient for either or both receptors (Immunex Corp., Seattle, WA) to study the role of TNF-α in the dimethylnitrosamine (DMN) model. Mice exposed to DMN showed a dose-dependent increase in liver damage as determined by histopathology and the presence of liver enzymes in serum. Compared to TNFR intact mice, mice deficient for TNFR55 showed greatly reduced hepatocellular disruption for up to 5 exposures. TNFR75 knockout mice and TNFR55/75 knockout mice were protected from hepatotoxicity to a lesser extent. However, by 7 exposures, TNFR55 knockout mice were no longer protected from DMN-induced liver damage, and TNFR55/75 knockout mice were dramatically more affected. In addition, accumulation of inflammatory cells in hepatic lesions was greatly reduced by the TNFR75 gene knockout. This suggests that the effects of TNF-α may differ between acute and chronic exposures, and that the deleterious effects of TNF-α in acute exposure is mediated through TNFR55. We have further examined hepatic gene expression during DMN exposure using differential display-reverse transcriptase-PCR (DDRT-PCR). We have identified several transcripts which are induced by DMN treatment, several of which are differentially expressed by TNFR intact and TNFR75 knockout mice. Characterization of these transcripts will be reported.

Original languageEnglish (US)
Pages (from-to)A1330
JournalFASEB Journal
Issue number6
StatePublished - 1996
Externally publishedYes

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics


Dive into the research topics of 'Role of tnf-α in dimethylnitrosamine-induced hepatotoxicity'. Together they form a unique fingerprint.

Cite this