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NFκB‐mediated upregulation of bcl‐xl restrains TRAIL‐mediated apoptosis in murine viral hepatitis
Author(s) -
Zender Lars,
Hütker Sebastian,
Mundt Bettina,
Waltemathe Morlen,
Klein Christian,
Trautwein Christian,
Malek Nisar P.,
Manns Michael Peter,
Kühnel Florian,
Kubicka Stefan
Publication year - 2005
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.20566
Subject(s) - downregulation and upregulation , apoptosis , bcl xl , cancer research , nf κb , hepatitis b virus , fas ligand , programmed cell death , immunology , virology , medicine , biology , virus , biochemistry , gene
Inhibition of NFκB enhances the susceptibility of cancer to TRAIL‐mediated apoptosis and is suggested as a strategy for cancer therapy. Because the role of NFκB in TRAIL‐mediated apoptosis of hepatocytes is unknown, we investigated the influence of NFκB‐inhibition in death ligand‐mediated apoptosis in hepatitis. Adenoviral hepatitis resulted in upregulation of NFκB‐activity, which could be inhibited by expression of IκBα‐superrepressor. We treated mice after the onset of adenoviral hepatitis with adenoviruses expressing FasL (AdFasL), TRAIL (AdTRAIL), or GFP (AdGFP). In contrast to apoptosis induced by AdFasL, NFκB inhibition strongly enhanced AdTRAIL‐mediated apoptosis of hepatocytes. Expression of IκBα inhibits adenoviral infection‐mediated overexpression of bcl‐xl, providing a molecular mechanism for TRAIL sensitization. In agreement with this hypothesis, downregulation of bcl‐xl by siRNA enhanced susceptibility of hepatocytes to TRAIL, but not to FasL‐mediated apoptosis, resulting in TRAIL‐mediated severe liver damage after AdTRAIL application. Our data demonstrate that inhibition of NFκB in adenoviral hepatitis strongly sensitizes hepatocytes to TRAIL‐mediated apoptosis. Bcl‐xl, in contrast to bcl‐2 and c‐FLIP, is strongly upregulated after viral infection and represents an essential NFκB‐dependent survival factor against TRAIL‐mediated apoptosis. In conclusion , inhibition of NFκB or bcl‐xl during TRAIL therapy may harbor a risk of liver damage in patients with viral hepatitis. (H EPATOLOGY 2005;41:280–288.)