PMID- 21533085
OWN - NLM
STAT- MEDLINE
DCOM- 20110830
LR  - 20181113
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 6
IP  - 4
DP  - 2011 Apr 20
TI  - Modeling the TNFalpha-induced apoptosis pathway in hepatocytes.
PG  - e18646
LID - 10.1371/journal.pone.0018646 [doi]
AB  - The proinflammatory cytokine TNFalpha fails to provoke cell death in isolated
      hepatocytes but has been implicated in hepatocyte apoptosis during liver diseases
      associated with chronic inflammation. Recently, we showed that TNFalpha is able
      to sensitize primary murine hepatocytes cultured on collagen to Fas
      ligand-induced apoptosis and presented a mathematical model of the sensitizing
      effect. Here, we analyze how TNFalpha induces apoptosis in combination with the
      transcriptional inhibitor actinomycin D (ActD). Accumulation of reactive oxygen
      species (ROS) in response to TNFR activation turns out to be critical for
      sustained activation of JNK which then triggers mitochondrial pathway-dependent
      apoptosis. In addition, the amount of JNK is strongly upregulated in a
      ROS-dependent way. In contrast to TNFalpha plus cycloheximide no cFLIP
      degradation is observed suggesting a different apoptosis pathway in which the
      Itch-mediated cFLIP degradation and predominantly caspase-8 activation is not
      involved. Time-resolved data of the respective pro- and antiapoptotic factors are
      obtained and subjected to mathematical modeling. On the basis of these data we
      developed a mathematical model which reproduces the complex interplay regulating
      the phosphorylation status of JNK and generation of ROS. This model was fully
      integrated with our model of TNFalpha/Fas ligand sensitizing as well as with a
      published NF-kappaB-model. The resulting comprehensive model delivers insight in
      the dynamical interplay between the TNFalpha and FasL pathways, NF-kappaB and ROS
      and gives an example for successful model integration.
FAU - Schlatter, Rebekka
AU  - Schlatter R
AD  - Institute for System Dynamics, University of Stuttgart, Stuttgart, Germany.
FAU - Schmich, Kathrin
AU  - Schmich K
FAU - Lutz, Anna
AU  - Lutz A
FAU - Trefzger, Judith
AU  - Trefzger J
FAU - Sawodny, Oliver
AU  - Sawodny O
FAU - Ederer, Michael
AU  - Ederer M
FAU - Merfort, Irmgard
AU  - Merfort I
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110420
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (DNA Primers)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 1CC1JFE158 (Dactinomycin)
RN  - 9007-43-6 (Cytochromes c)
SB  - IM
MH  - Animals
MH  - Apoptosis/*physiology
MH  - Base Sequence
MH  - Blotting, Western
MH  - Cytochromes c/metabolism
MH  - DNA Primers
MH  - Dactinomycin/pharmacology
MH  - Enzyme Activation
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Hepatocytes/*cytology/drug effects/enzymology/metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - *Models, Biological
MH  - Reactive Oxygen Species/metabolism
MH  - Tumor Necrosis Factor-alpha/*physiology
PMC - PMC3080376
EDAT- 2011/05/03 06:00
MHDA- 2011/08/31 06:00
CRDT- 2011/05/03 06:00
PHST- 2010/10/07 00:00 [received]
PHST- 2011/03/14 00:00 [accepted]
PHST- 2011/05/03 06:00 [entrez]
PHST- 2011/05/03 06:00 [pubmed]
PHST- 2011/08/31 06:00 [medline]
AID - 10.1371/journal.pone.0018646 [doi]
PST - epublish
SO  - PLoS One. 2011 Apr 20;6(4):e18646. doi: 10.1371/journal.pone.0018646.