Hepatocellular proliferation in response to a peroxisome proliferator does not require TNFalpha signaling.
Rodents exposed to peroxisome proliferator xenobiotics respond with marked increases in hepatocellular replication and growth that results in tumor formation. Recently, tumor necrosis factor-alpha (TNFalpha) was proposed as the central mediator of this maladaptive response. To define the role of TNFalpha signaling in hepatocellular growth induced by peroxisome proliferators we administered three daily gavage doses of the potent peroxisome proliferator, Wy-14 643, to mice nullizygous for TNF-receptor I (TNFR1), TNFR2, or both receptors. We demonstrate here that regardless of genotype the mice responded with almost identical increases in liver to body weight ratios and hepatocyte proliferation. Lacking evidence that TNFalpha signaling mediates these effects, we then examined the possible contribution of alternative cytokine pathways. Semi-quantitative, reverse transcriptase polymerase chain reaction analysis revealed that wild type mice acutely exposed to Wy-14 643 had increased hepatic expression of Il1beta, Il1r1, Hnf4, and Stat3 genes. Moreover, hepatic adenomas from mice chronically exposed to Wy-14 643 had increased expression of Il1beta, Il1r1, Il6, and Ppargamma1. Expression of Il1alpha, Tnfalpha, Tnfr1, Tnfr2, Pparalpha, or C/ebpalpha was not altered by acute Wy-14 643 exposure or in adenomas induced by Wy-14643. These data suggest that the hepatic mitogenesis and carcinogenesis associated with peroxisome proliferator exposure is not mediated via TNFalpha but instead may involve an alternative pathway requiring IL1beta and IL6.
Anderson
S P
SP
CIIT Centers for Health Research, Research Triangle Park, NC 27709, USA.
Dunn
C S
CS
Cattley
R C
RC
Corton
J C
JC
D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry; D004268:DNA-Binding Proteins; D051557:Hepatocyte Nuclear Factor 4; D007375:Interleukin-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008099:Liver / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020025:Peroxisome Proliferators / Q000494:pharmacology*; D020675:Peroxisomes / Q000187:drug effects / Q000648:ultrastructure; D010750:Phosphoproteins / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D012313:RNA / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D017931:DNA Primers; D004268:DNA-Binding Proteins; D051557:Hepatocyte Nuclear Factor 4; D007375:Interleukin-1; D015850:Interleukin-6; D020025:Peroxisome Proliferators; D010750:Phosphoproteins; D011743:Pyrimidines; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C501970:Tcfl4 protein, mouse; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D012313:RNA; C006253:pirinixic acid; D004247:DNA