Tumour necrosis factor alpha (TNFalpha): role in suppression of apoptosis by the peroxisome proliferator nafenopin.
The peroxisome proliferator (PPs) class of non-genotoxic rodent hepatocarcinogens induce mouse hepatocyte DNA synthesis and suppress apoptosis. This phenotype can be reproduced in vitro using exogenous tumour necrosis factor alpha (TNFalpha), suggesting a role for TNFalpha in mediating the liver growth response to PPs. In hepatocytes isolated from the peroxisome proliferator activated receptor alpha (PPARalpha) null mouse, PPs are unable to stimulate DNA synthesis or to suppress either spontaneous or TGFbeta1-induced apoptosis. However, the ability of TNFalpha to modulate hepatocyte survival and growth is unaltered, suggesting that TNFalpha acts independently or downstream of PPARalpha to mediate the growth changes associated with PPARalpha activation. Since PPARalpha is a ligand activated transcription factor, we determined if TNFalpha gene expression was altered by PP treatment during an early time window preceding PP-induced growth changes. However there was no induction of TNFalpha expression by nafenopin over the constitutive levels noted in control cultured cells. In summary, TNFalpha acts downstream or independently of PPARalpha to mediate the suppression of apoptosis and induction of DNA synthesis by PPs. In this in vitro model, the PP nafenopin do not appear to mediate de novo TNFalpha gene expression suggesting that the response to nafenopin may be mediated by bioactivation or release of pre-existing TNFalpha protein from Kupffer cells.
Holden
P R
PR
Cancer Biology, Zeneca Central Toxicology Laboratory, Alderley Park, Macclesfield, UK.
Hasmall
S C
SC
James
N H
NH
West
D R
DR
Brindle
R D
RD
Gonzalez
F J
FJ
Peters
J M
JM
Roberts
R A
RA
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D004261:DNA Replication / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009255:Nafenopin / Q000494:pharmacology*; D020025:Peroxisome Proliferators / Q000494:pharmacology*; D020675:Peroxisomes / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D020025:Peroxisome Proliferators; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D009255:Nafenopin