Role of MAP kinase signalling pathways in the mode of action of peroxisomeproliferators

Peroxisome proliferators (PPs) are a class of non-genotoxic chemicals that cause rodent liver enlargement and hepatocarcinogenesis. In primary rat hep atocytes, PPs cause cell proliferation, suppression of apoptosis and peroxi some proliferation. We have investigated the role of different families of mitogen-activated protein (MAP) kinases in the mode of action of PPs, Addit ion of 50 mu M nafenopin to primary rat hepatocyte cultures caused weak act ivation of extracellular signal regulated kinases and p38 MAP kinase. Howev er, incubation of primary hepatocytes with the p38 MAP kinase inhibitor SB2 03580 or the MAP kinase kinase (MEK) inhibitor PD098059 prevented the induc tion of DNA synthesis and the suppression of transforming growth factor bet a(1)-induced apoptosis by the PP nafenopin. In contrast, in the presence of these MAP kinase inhibitors, nafenopin still induced palmitoyl CoA oxidati on, a measure of peroxisome proliferation. We have shown previously that PP s such as nafenopin require tumour necrosis factor alpha (TNF-alpha) to exe rt their effects on cellular proliferation and apoptosis, Here me show that treatment of primary rat hepatocyte cultures,vith nafenopin causes an incr ease in bioactive TNF-alpha and that this process requires p38 MAP kinase a ctivity.