Liver tumor promotion by 2,3,7,8-tetrachlorodibenzo-p-dioxin is dependent on the aryl hydrocarbon receptor and TNF/IL-1 receptors.
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 Ahr(b1) or Ahr(d) 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.
Department of Surgery, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin 53792.
Gregory D
GD
Kennedy
Department of Surgery, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin 53792.
Manabu
M
Nukaya
McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, Wisconsin 53706.
Susan M
SM
Moran
McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, Wisconsin 53706.
Edward
E
Glover
McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, Wisconsin 53706.
Samuel
S
Weinberg
Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455.
Silvia
S
Balbo
Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455.
Stephen S
SS
Hecht
McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, Wisconsin 53706.
Henry C
HC
Pitot
McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, Wisconsin 53706.
Norman R
NR
Drinkwater
McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, Wisconsin 53706 bradfield@oncology.wisc.edu.
Christopher A
CA
Bradfield
D000818:Animals; D002210:Caprylates / Q000633:toxicity; D003043:Cocarcinogenesis; D004052:Diethylnitrosamine / Q000633:toxicity; D004147:Dioxins / Q000633:toxicity*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000276:immunology / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism*; D014280:Triglycerides / Q000633:toxicity
D002210:Caprylates; D004147:Dioxins; D018336:Receptors, Aryl Hydrocarbon; D017472:Receptors, Interleukin-1; D018124:Receptors, Tumor Necrosis Factor; D014280:Triglycerides; C066841:2,3,7,8-tetrabromodibenzo-4-dioxin; D004052:Diethylnitrosamine; C003637:tricaprylin
IL-1-like cytokine; aryl hydrocarbon receptor (AHR); dioxin; liver; tumor promotion