CD40 activation induces apoptosis in cultured human hepatocytes via induction of cell surface Fas ligand expression and amplifies Fas-mediated hepatocyte death during allograft rejection

We propose that a novel mechanism of hepatocyte apoptosis, involving a coop erative interaction between CD40 and Fas, is involved in the hepatocyte los s of chronic liver allograft rejection. We detected increased hepatocyte ex pression of Fas, Fas ligand (FasL), and CD40 associated with dropout of cen trilobular (acinar zone 3) hepatocytes in chronic allograft rejection. Expr ession of CD40 ligand (CD40L) was also increased but was largely restricted to CD68(+) macrophages. A functional role for CD40 and Fas in hepatocyte a poptosis was demonstrated in vitro using primary human hepatocytes and the HepG2 cell, line in both of which apoptosis was induced, not only by cross- linking Fas directly but also via CD40 activation. Our data suggest that CD 40 activation induces apoptosis via Fas because (a) ligation of CD40 upregu lated hepatocyte Fast expression, and (b) apoptosis induced via activation of CD40 was prevented by a neutralizing monoclonal antibody to Fast. Thus, CD40 engagement triggers apoptosis of human hepatocytes and might amplify F as-dependent hepatocyte apoptosis in chronic rejection and other inflammato ry liver diseases in which Fas-mediated apoptosis is involved.