TY  - GEN
ID  - heidok16427
Y1  - 2013///
TI  - IL-6 induzierte Signaltransduktion in HaCaT-ras A5 und Fibroblasten
A1  - Nici, Marco
AV  - public
UR  - https://archiv.ub.uni-heidelberg.de/volltextserver/16427/
N2  - The interactions between tumor cells and the microenvironment play a crucial role in tumor
progression. Tumor cells secrete growth factors, cytokines and proteases and are thus able
to affect the gene expression of stromal cells. Activate
d stromal cells like fibroblasts, immune
cells and endothelial cells are able to promote tumor progression by releasing growth factors,
cytokines and proteases. One of the factors which play a central role in this tumor
-
and
stroma
-
interaction is interleuk
in
-
6. In many tumor entities, the IL
-
6 signal
pathway is highly
dysregulated
by overexpression of IL
-
6 and otherwise by permanent activation of the
STAT3
transcription factor.
In this work, we showed that IL
-
6 stimulation resulted in an increased prolifera
tion of HaCaT
-
ras A5 benign tumor keratinocytes, but does not affect the fibroblast cell line MSU1.1.
This increase correlates with the activation of the JAK/STAT signaling pathway. We were
able to demonstrate that the amount of activated STAT3 proteins
after IL
-
6 stimulation in
HaCaT
-
ras A5 cells is strongly up regulated and the inhibition of STAT3 activation also
inhibits the proliferation of HaCaT
-
ras A5 cells. This showed the crucial role of the STAT3
activation in proliferation of HaCaT
-
ras A5 cells.
In contrast, fibroblasts showed a stronger inhibition of the JAK/STAT signal pathway by
SOCS3 in comparison with the HaCaT
-
ras A5 cells.
All data where used to establish a mathematical model of JAK/STAT pathway which is able
to describe the dynamic behav
ior of STAT3 and SOCS3 Proteins.
In addition to the effects shown, IL
-
6 is also able to affect the proliferation in an indirect
manner. To this end, IL
-
6 stimulation activates a network of growth factors in HaCaT
-
ras A5
cells and fibroblasts like HGF, KGF
, VEGF or IL
-
8. While IL
-
6 showed no direct influence of
the proliferation of fibroblasts, the addition of the condition media of both IL
-
6 stimulated
HaCaT
-
ras A5 and as well as IL
-
6 stimulated MSU1.1 resulted in strong up regulation of the
cell numbers o
f the other cell line.
Comparative gene expression analyses clearly showed that upon IL
-
6 stimulation of over
16000 analyzed genes in HaCaT
-
ras A5 and Fibroblasts only a subset of 19 genes was up
regulated in both cell types. The up regulated genes were f
ound to be closely connected with
the interferon signal pathway which gives a potential hint of the cause of the IL
-
6 induced
inhibition of growth in fibroblasts.
Further gene expression analyses showed that the proteinase inhibitor SerpinB4, was
permanent
ly up regulated in IL
-
6 stimulated HaCaT
-
ras A5 cells. The down regulation of
Summary
9
SerpinB4 by siRNA knockdown indicated that SerpinB4 plays an important role in the
proliferation of HaCaT
-
ras A5.
The observation of this work of the detailed regulation of IL
-
6
in tumor and stroma cells
should give information about the tumor promoting effect of IL
-
6 and will ultimately serve as a
basis for therapeutic therapies.
ER  -