Involvement of TRAIL and its receptors in viral hepatitis.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is able to kill a broad spectrum of tumor cells but appears to be nontoxic to most normal cells. Because there are conflicting data about the hepatotoxicity of TRAIL, we investigated the physiological function of TRAIL and its receptors in the liver. Hepatocytes are sensitive for FasL- and TRAIL-mediated apoptosis in vitro, but TRAIL induces no apoptosis in healthy livers in vivo. Using mouse models of adenoviral hepatitis and livers of patients with hepatitis infection, we could demonstrate that apoptosis in virally infected hepatocytes is mediated by TRAIL receptor DR5 and TRAIL. In contrast to FasL, TRAIL-mediated apoptosis of hepatocytes in vivo is triggered through viral infection. The TRAIL receptor/ligand system enables the organisms to specifically kill virus-infected hepatocytes, whereas normal uninfected hepatocytes in vivo are resistant to TRAIL-mediated apoptosis. Overexpression of TRAIL in the liver after viral infection is not dependent on lymphocytes, natural killer, or Kupffer cells, which indicates that the TRAIL receptor/ligand system is a paracrine mechanism of hepatocytes against virally infected cells. Our results suggest that TRAIL might be used not only for cancer therapy but also for therapy of patients with viral hepatitis to selectively eliminate infected hepatocytes and limit viral replication.