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liver regeneration. Deficiency in complement C3 and C5 is associated
with impaired liver regeneration following hepatectomy. This
slower regeneration process is due to the suppressed activation of
STAT3 and AKT (
79
). These results again highlight the impor-
tance of these signaling pathways in liver regeneration.
As mentioned above, hepatocytes are among the few cell types,
which express IL-6R and are therefore responsive to the cytokine
IL-6. Therefore, it was puzzling that IL-6/sIL-6R double trans-
genic mice showed massive hepatocyte proliferation even without
hepatectomy, whereas IL-6 single transgenic mice did not show
such a phenotype (
74, 75, 80
). Although these findings were in
line with the fact that injection of IL-6 alone did not accelerate
liver regeneration, the application of Hyper-IL-6 resulted in a dras-
tic amplification of the liver regeneration response (
26, 27, 64
).
This apparent contradiction is explained by the fact that hepato-
cytes, like most IL-6R expressing cells, express far more gp130 on
the cell surface than IL-6R (Fig.
4
). Stimulation with IL-6 alone
leads to STAT3 activation and a subsequent IL-6 response. In the
presence of Hyper-IL-6, however, far more gp130 molecules are
stimulated leading to a more profound STAT3 activation and
response. We have shown that the presence of sIL-6R renders IL-6
responsive cells far more sensitive to IL-6 in vitro and in vivo (
81,
82
). We therefore speculate that for the onset of hepatocyte prolif-
eration, a threshold of activated STAT3 proteins has to be over-
come and that this threshold is not reached when stimulation with
IL-6 alone occurs (
26, 27, 64, 75, 80
).
6
The Effect of IL6-gp130 on Stem Cells
The spontaneous differentiation of mouse embryonic stem cells can
be blocked by the gp130 cytokine LIF. Upon the activation of
gp130 by LIF—the STAT3 pathway is activated. The role of STAT3
in stemness was previously reported (
61
). STAT3 promotes the
expression of KLF4 and Nanog, although not all investigations
agree with this observation. Recent reports further indicate the
importance of STAT3 signaling in pluripotency. STAT3 was shown
to be responsible for the conversion of EpiSC back to embryonic
stem cells (
83
). The role of signaling and trans-signaling in murine
and human embryonic stem cells showed that gp130 stimulation
activated the three downstream pathways of ERK, AKT and STAT3,
although it did not prevent the loss of pluripotent markers in human
cells (
39
). These conflicting results and the exact role of IL-6 still
awaits further investigation to better determine the role of IL-6 sig-
naling and trans-signaling in controlling stemness-differentiation-
proliferation of embryonic stem cells. We have shown that in murine
embryonic stem cells, a prolonged gp130 stimulation—mimicking
the effect of hyper IL6/IL6 trans-signaling, prevented differentia-
tion and supported stemness through STAT3 activation (
84
).
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