CD154-CD40 interactions drive hepatocyte apoptosis in murine fulminant hepatitis

The CD154-CD40 interaction is a critical costimulatory pathway modulating the cellular immune response. Moreover, fulminant hepatitis of various etiologies is characterized by a hepatic influx of CD154-expressing T cells and an upregulation of CD40 expression on Kupffer cells and hepatocytes, implicating this pathway in the pathogenesis of fulminant hepatitis. In this study, we used a murine model of fulminant hepatitis induced by concanavalin A (con A) and documented a significant influx of CD154-expressing T cells into the livers of mice treated with con A, in association with markedly increased expression of CD40 restricted mainly to hepatocytes in damaged areas of the liver. Furthermore, con A hepatitis in CD154-deficient mice was significantly attenuated compared with that in wild-type controls and was associated with a decrease in hepatic tumor necrosis factor alpha (TNF-alpha) levels and hepatocyte death. We next determined the role of the CD154-CD40 pathway in hepatocyte death in vitro. These in vitro studies demonstrated that TNF-alpha induces CD40 expression in hepatocytes and that subsequent activation of CD40 results in hepatocyte apoptosis mediated at least in part by enhanced hepatocyte expression of FasL. In conclusion, CD154 stimulation of CD40 plays a central role in hepatocyte death in fulminant hepatitis through direct and indirect pathways that may have direct therapeutic implications in humans. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html).