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@ARTICLE{Faletti:137579,
author = {L. Faletti and L. Peintner and S. Neumann and S. Sandler
and T. Grabinger and S. Mac Nelly and I. Merfort and C.-H.
Huang and D. F. Tschaharganeh$^*$ and T.-W. Kang$^*$ and F.
Heinzmann$^*$ and L. D'Artista$^*$ and U. Maurer and T.
Brunner and S. Lowe and L. Zender$^*$ and C. Borner},
title = {{TNF}α sensitizes hepatocytes to {F}as{L}-induced
apoptosis by {NF}κ{B}-mediated {F}as upregulation.},
journal = {Cell death $\&$ disease},
volume = {9},
number = {9},
issn = {2041-4889},
address = {London [u.a.]},
publisher = {Nature Publishing Group},
reportid = {DKFZ-2018-01459},
pages = {909},
year = {2018},
abstract = {Although it is well established that TNFα contributes to
hepatitis, liver failure and associated hepatocarcinogenesis
via the regulation of inflammation, its pro-apoptotic role
in the liver has remained enigmatic. On its own, TNFα is
unable to trigger apoptosis. However, when combined with the
transcriptional inhibitor GaLN, it can cause hepatocyte
apoptosis and liver failure in mice. Moreover, along with
others, we have shown that TNFα is capable of sensitizing
cells to FasL- or drug-induced cell death via c-Jun
N-terminal kinase (JNK) activation and
phosphorylation/activation of the BH3-only protein Bim. In
this context, TNFα could exacerbate hepatocyte cell death
during simultaneous inflammatory and T-cell-mediated immune
responses in the liver. Here we show that TNFα sensitizes
primary hepatocytes, established hepatocyte cell lines and
mouse embryo fibroblasts to FasL-induced apoptosis by the
transcriptional induction and higher surface expression of
Fas via the NFκB pathway. Genetic deletion, diminished
expression or dominant-negative inhibition of the NFκB
subunit p65 resulted in lower Fas expression and inhibited
TNFα-induced Fas upregulation and sensitization to
FasL-induced cell death. By hydrodynamic injection of p65
shRNA into the tail vein of mice, we confirm that Fas
upregulation by TNFα is also NFκB-mediated in the liver.
In conclusion, TNFα sensitization of FasL-induced apoptosis
in the liver proceeds via two parallel signaling pathways,
activation of JNK and Bim phosphorylation and NFκB-mediated
Fas upregulation.},
cin = {F190 / V076 / L801},
ddc = {570},
cid = {I:(DE-He78)F190-20160331 / I:(DE-He78)V076-20160331 /
I:(DE-He78)L801-20160331},
pnm = {316 - Infections and cancer (POF3-316)},
pid = {G:(DE-HGF)POF3-316},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:30185788},
pmc = {pmc:PMC6125596},
doi = {10.1038/s41419-018-0935-9},
url = {https://inrepo02.dkfz.de/record/137579},
}