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All three IL-6 signaling pathways (STAT3, AKT, and ERK1/2) are
involved in the expression of pro-survival and cell proliferation genes.
Under these conditions, sIL-6R is generated leading to the forma-
tion of IL-6/sIL-6R complexes (
18, 67, 68
). These can act on any
tissue due to the fact that gp130 is ubiquitously expressed on all
mammalian cells. Leukocytes that are instantly migrating to an acute
injured tissue, be it an ischemic tissue in the heart or a liver following
hepatectomy, undergo apoptosis at the site of necrosis (
69
). While
undergoing apoptosis, leukocytes shed their IL-6R. This local event
enables the local complex formation of IL-6/sIL-6R that signals
through gp130 to initiate tissue regeneration. To simulate this “late”
event of the IL-6/sIL-6R complex generation, we used the designer
protein hyper IL-6. Administration of hyper IL-6 to mice and rats
has shown to potently induce regeneration in the liver (
65
), kidney
(
66
), and salivary gland (unpublished results). Furthermore, we
have been recently able to show (unpublished results) that on car-
diomyocytes, hyper IL-6 induces a >100-fold stronger phosphoryla-
tion of STAT 3 than of IL-6 itself. This result is in agreement with a
previous report showing a reduced infarct size following the admin-
istration of the IL-6/sIL-6R complex (
70
).
5
Liver Regeneration: The Role of the IL6-gp130 Pathway
Liver regeneration is a complex physiological process in which both
networks of molecular and cellular factors participate. The regen-
erative process includes both parenchymal and non-parenchymal
cells. Although it is becoming clearer in recent years that tissue
stem cells harbor many organs, their role in tissue regeneration is
still debatable. In the liver, the role of liver stem cells/progenitors
in the regenerative process might be even more convoluted. On
the one hand, there is growing evidence that STAT3 activation is
important in various stem cell physiology and propagation and on
the other hand, it is apparent that in an acute regeneration model,
liver stem cells probably contribute minimally to the liver regen-
erative process (
71
). One more important point which should be
mentioned is that most of our data on the role of IL-6-gp130
signaling in liver regeneration is deduced from 2/3 partial hepa-
tectomy (
72
), and not all investigators are using similar protocols,
animal or animal house environments, which might have a major
influence on results and conclusions. Consequently not all obser-
vations overlap.
Following partial hepatectomy in a healthy mouse, the liver
regenerates during a week to ten days and thereby returns to its
original size. The peak of cell DNA synthesis is about 40 h follow-
ing hepatectomy. Priming of regeneration is dependent on TNF
α
and IL-6 produced and released from non-parenchymal cells
including Kupffer cells and endothelial cells. This priming is
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