A dominant negative form of IKK2 prevents suppression of apoptosis by the peroxisome proliferator nafenopin

Peroxisome proliferators (PPs) are a class of non-genotoxic chemicals that cause rodent liver enlargement and hepatocarcinogenesis. In primary rat hep atocyte cultures, PPs suppress spontaneous apoptosis and that induced by a number of pro-apoptotic stimuli such as transforming growth factor-beta(1). Tumour necrosis factor alpha (TNF-alpha) and the transcription factor NF k appa B have been implicated in the mode of action of PPs, TNF-alpha signall ing to NF kappa B is thought to be responsible for many of the effects elic ited by this cytokine, NF kappa B regulates gene expression in immunity, st ress responses and the inhibition of apoptosis, Activation of NF kappa B re quires the successive action of NF kappa B-inducing kinase and the phosphor ylation of NF kappa B inhibitory proteins (I kappa B) by an I kappa B kinas e (IKK) complex. The IKK2. subunit of I kappa B kinase is thought to be ess ential for NF kappa B activation and prevention of apoptosis, To determine whether IKK2 plays a role in the suppression of apoptosis by PPs, we expres sed a dominant negative form of IKK2 (IKK2dn) in primary rat hepatocyte cul tures. Infection with an adenovirus construct expressing IKK2dn caused apop tosis in control primary rat hepatocytes in the absence of exogenous TNF-al pha. Moreover, IKK2dn-induced apoptosis could not be rescued by addition of TNF-alpha or the peroxisome proliferator nafenopin, These results demonstr ate a requirement for intracellular signalling pathways mediated by IKK2 in the suppression of apoptosis by the PP class of hepatocarcinogens.