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Brief Definitive Reports

Simon C. Afford^*, Satinder Randhawa^*, Aristides G. Eliopoulos, Stefan G. Hubscher, Lawrence S. Young, and David H. Adams^*

From the ^* Liver Research Laboratories, The University of Birmingham, Institute of Clinical Science, Queen Elizabeth Hospital, Birmingham B15 2TH, United Kingdom; the CRC Institute for Cancer Studies, The University of Birmingham Medical School, Edgbaston, Birmingham B15 2TJ, United Kingdom; and the Department of Pathology, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom

We propose that a novel mechanism of hepatocyte apoptosis, involving a cooperative interaction between CD40 and Fas, is involved in the hepatocyte loss of chronic liver allograft rejection. We detected increased hepatocyte expression of Fas, Fas ligand (FasL), and CD40 associated with dropout of centrilobular (acinar zone 3) hepatocytes in chronic allograft rejection. Expression of CD40 ligand (CD40L) was also increased but was largely restricted to CD68⁺ macrophages. A functional role for CD40 and Fas in hepatocyte apoptosis 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 CD40 activation induces apoptosis via Fas because (a) ligation of CD40 upregulated hepatocyte FasL expression, and (b) apoptosis induced via activation of CD40 was prevented by a neutralizing monoclonal antibody to FasL. Thus, CD40 engagement triggers apoptosis of human hepatocytes and might amplify Fas-dependent hepatocyte apoptosis in chronic rejection and other inflammatory liver diseases in which Fas-mediated apoptosis is involved.

Key Words: CD40 activation • apoptosis • hepatocytes • allograft rejection

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