Tumour necrosis factor alpha (TNF alpha): Role in suppression of apoptosisby the peroxisome proliferator nafenopin

The peroxisome proliferator (PPs) class of non-genotoxic rodent hepatocarci nogens induce mouse hepatocytes DNA synthesis and suppress apoptosis, This phenotype can be reproduced in vitro using exogenous tumour necrosis factor alpha (TNF alpha), suggesting a role for TNF alpha in mediating the liver growth response to PPs. In hepatocytes isolated from the peroxisome prolife rator activated receptor alpha (PPAR alpha) null mouse, PPs are unable to s timulate DNA synthesis or to suppress either spontaneous or TCF beta 1-indu ced apoptosis. However, the ability of TNF alpha to modulate hepatocyte sur vival and growth is unaltered, suggesting that TNF alpha acts independently or downstream of PPAR alpha to mediate the growth changes associated with PPAR alpha activation. Since PPAR alpha is a ligand activated transcription factor, we determined if TNF alpha gene expression was altered by PP treat ment during an early time window preceding PP-induced growth changes. Howev er there was no induction of TNF alpha expression by nafenopin over the con stitutive levels noted in control cultured cells. In summary, TNF alpha act s downstream or independently of PPAR alpha to mediate the suppression of a poptosis and induction of DNA synthesis by PPs. In this in vitro model, the PP nafenopin do nor appear to mediate de novo TNF alpha gene expression su ggesting that the response to nafenopin may be mediated by bioactivation or release of pre-existing TNF alpha protein from Kupffer cells.