Background and aim: It is well known that tumor necrosis factor-alpha (TNF-alpha) induces hepatocyte apoptosis and contributes to liver diseases. However, the exact mechanisms are not well understood.
Methods: In the present study, we reported that Na(+)/H(+) exchanger (NHE) is involved in TNF-alpha-induced hepatocyte apoptosis.
Results: TNF-alpha time dependently induced an increase in NHE activity in hepatocytes, but cariporide, an NHE inhibitor, blocked the TNF-alpha-induced increase of NHE activity in a dose-dependent manner. Increased NHE activity induced by TNF-alpha was associated with increased intracellular calcium (Ca(2+)(i)) concentration and calpain activity. Cariporide reversed these effects induced by TNF-alpha. In addition, TNF-alpha downregulated Bcl-xL, an anti-apoptotic protein, but not mRNA levels. The inhibition of either calpain or NHE blocked the TNF-alpha-induced decrease of the Bcl-xL protein. TNF-alpha did not change the pro-apoptotic Bax and Bak protein levels. Cariporide, calcium remover 1,2-bis (2-aminophenoxy) ethane-N,N,N0,N0-tetraacetic acid, or calpain inhibitor benzyloxycarbonyl-leucyl-leucinal attenuated TNF-alpha-induced hepatocyte apoptosis.
Conclusion: TNF-alpha via NHE results in hepatocyte apoptosis through the calcium/calpain/Bcl-xL pathway.