Liver tumor promotion by 2,3,7,8-tetrachlorodibenzo-p-dioxin is dependent on the aryl hydrocarbon receptor and TNF/IL-1 receptors

Gregory D. Kennedy, Manabu Nukaya, Susan M. Moran, Edward Glover, Samuel Weinberg, Silvia Balbo, Stephen S. Hecht, Henry C. Pitot, Norman R. Drinkwater, Christopher A. Bradfield

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

We set out to better understand the signal transduction pathways that mediate liver tumor promotion by 2,3,7,8-tetrachlorodibenzo-p-dioxn ("dioxin"). To this end, we first employed congenic mice homozygous for either the Ahrb1 or Ahrd alleles (encoding an aryl hydrocarbon receptor (AHR) with high or low binding affinity for dioxin, respectively) and demonstrated that hepatocellular tumor promotion in response to dioxin segregated with the Ahr locus. Once we had genetic evidence for the importance of AHR signaling, we then asked if tumor promotion by dioxin was influenced by "interleukin-1 (IL-1)-like" inflammatory cytokines. The importance of this question arose from our earlier observation that aspects of the acute hepatocellular toxicity of dioxin are dependent upon IL1-like cytokine signaling. To address this issue, we employed a triple knock-out (TKO) mouse model with null alleles at the loci encoding the three relevant receptors for tumor necrosis factors α and β and IL-1α and IL-1β (i.e., null alleles at the Tnfrsf1a, Tnfrsf1b, and Il-1r1 loci). The observation that TKO mice were resistant to the tumor promoting effects of dioxin in liver suggests that inflammatory cytokines play an important step in dioxin mediated liver tumor promotion in the mouse. Collectively, these data support the idea that the mechanism of dioxin acute hepatotoxicity and its activity as a promoter in a mouse two stage liver cancer model may be similar, i.e., tumor promotion by dioxin, like acute hepatotoxicity, are mediated by the linked action of two receptor systems, the AHR and the receptors for the "IL-1-like" cytokines.

Original languageEnglish (US)
Pages (from-to)135-143
Number of pages9
JournalToxicological Sciences
Volume140
Issue number1
DOIs
StatePublished - Jul 2014

Keywords

  • Aryl hydrocarbon receptor (AHR)
  • Dioxin
  • IL-1-like cytokine
  • Liver
  • Tumor promotion

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