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A more recent version of this article appeared on April 1, 2003
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Submitted on July 4, 2002
Revised on November 29, 2002
Accepted on December 26, 2002
B and AP-1 Activity Following CD40 Ligation is Associated with Primary Human Hepatocyte Apoptosis or Intrahepatic Endothelial Cell Proliferation
1 Liver Research Laboratories, MRC Centre for Immune Regulation, University of Birmingham Institute of Clinical Science, Queen Elizabeth Hospital, Vincent Drive, Edgbaston, Birmingham, B15 2TH, United Kingdom
2 CRC Institute for Cancer Studies, The University of Birmingham Medical School, Birmingham, B15 2TT, United Kingdom
* Corresponding author. E-mail address: S.C.Afford{at}bham.ac.uk.
CD40, a TNF receptor superfamily member, is upregulated on endothelial and epithelial cells during inflammatory liver disease, and there is evidence that the functional outcome of CD40 ligation differs between cell types. Ligation of CD40 on cholangiocytes or hepatocytes results in induction of Fas-mediated apoptosis, whereas ligation of endothelial cell CD40 leads to enhanced chemokine secretion and adhesion molecule expression. We now report that differential activation of two transcription factors, NF-
B and AP-1, in primary human hepatocytes or intrahepatic endothelial cells is associated with and may explain, in part, the different responses of these cell types to CD40 ligation.
CD40 ligation induced a rise in NF-B activity in hepatocytes which peaked at 2 hours and returned to baseline by 24 hours, however, endothelial cell CD40 ligation resulted in a sustained upregulation of NF-B (over 24 hours). In hepatocytes, CD40 ligation led to sustained upregulation of AP-1 activity over 24 hours associated with increased protein levels of RelA (p65), c-Jun and c-Fos, whereas no induction of AP-1 activity was observed in endothelial cells. Analysis of MAPK phosphorylation (pERK1/2 and pJNK1/2) and expression of IB-
were entirely consistent, and thus confirmed the profiles of NF-B and AP-1 signalling and the effects of the selective inhibitors assessed using EMSA or Western immunoblotting. CD40 ligation resulted in induction of apoptosis in hepatocytes after 24-hours, but on endothelial cells, CD40 ligation resulted in proliferation. Inhibition of [CD40-mediated] NF-B activation prevented endothelial cell proliferation and led to induction of apoptosis. Selective ERK and JNK inhibitors reduced levels of apoptosis in [CD40-stimulated] hepatocytes by approximately 50%. We conclude that differential activation of these two transcription factors in response to CD40 ligation is associated with differences in cell fate. Transient activation of NF-B and sustained AP-1 activation is associated with apoptosis in hepatocytes, whereas prolonged NF-B activation and a lack of AP-1 activation in endothelial cells results in proliferation.
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