Signaling pathway underlying the up-regulatory effect of TNF-α on the Na+/K+ ATPase in HepG2 cells

The activity of the Na+/K+ ATPase was shown to be reduced during apoptosis and enhanced during cell proliferation. This work investigated whether TNF-α exerts also opposite effects on the Na+/K+ ATPase in HepG2 cells and whether these effects are time-dependent. A time response study demonstrated that the activity and protein expression of the ATPase are decreased at 1 h and increased at 4, 6 and 8 h. This work focused on the up-regulatory 4 h-response. TNF-α was shown to exert a stimulatory effect on cJNK and NF-κB and an inhibitory effect on caspases which, in the basal state, down-regulate the ATPase. The cytokine was found to target the caspases by activating JNK which in turn activates NF-κB. The activated transcription factor inhibits the caspases and frees the ATPase from their inhibitory action leading thus to its up-regulation.