Biology Reference
In-Depth Information
Using knock-in mouse technology, the juxtamembrane tyrosine
residue of mouse gp130 was exchanged for phenylalanine. In a
second knock-in mouse, the portion of gp130 containing the four
membrane-distal tyrosine residues of gp130 was deleted. Thus,
two mouse lines were available, one of which was incapable of acti-
vating SHP2 and subsequently the ras/ERK and the PI3K/AKT
pathways, whereas the other mouse line was unable to activate the
STAT pathway upon gp130 stimulation (
59
). These mouse lines
were widely used to unravel the importance of the two signaling
pathways triggered by gp130 activation.
The stimulation of embryonic stem cells with the gp130 cytokine
LIF leads to a complete block of cellular differentiation, which is a
prerequisite for the generation of knock-out mice, since default dif-
ferentiation of these cells during the homologous recombination
procedure can be prevented (
60
). The same block of differentiation
was shown to occur in murine embryonic stem cells treated with
Hyper-IL-6 indicating that only gp130 stimulation was required for
this cellular response (
39, 40
). Activation of STAT3 was shown to be
sufficient to maintain an undifferentiated state of mouse embryonic
stem cells (
61
). It has been as, however, shown recently that the
requirement for STAT3 activation can also be bypassed by the elimi-
nation of differentiation-inducing signaling from MAP kinase (
62
).
The activity of gp130 to block differentiation has been used in the
expansion of hematopoietic stem cells. Here, the cells were treated
with hematopoietic cytokines such as SCF and Flt3-L in the pres-
ence of IL-6 or Hyper-IL-6. It turned out that Hyper-IL-6 led to a
much more efficient expansion of hematopoietic stem cells as com-
pared to IL-6 (
25, 32-35, 37, 38
).
An additional activity of IL-6 is the prevention of apoptosis in
many cell types including hematopoietic cells, neural cells, epithe-
lial cells and tumor cells (
55
). Due to the low or lacking IL-6R
expression levels on most cells, this activity of IL-6 frequently
depends on the presence of the sIL-6R (
22, 55
).
4
IL-6 Signaling and Trans-signaling in Tissue Regeneration
The restoration of the physiological function following injury to
tissue is a complex process. The mediator of such a process and the
target cells are only partially known for each and every type of tis-
sue and injury. The cells participating in the regenerative process
could originate from different populations inside and outside of
any specific organ. The cell types potentially involved in tissue
regeneration include the following: (1) Tissue mature parenchy-
mal cells, e.g., in the kidney, tubular epithelium cells. (2) Tissue
progenitor/stem cells, e.g., cardiac stem cells. (3) Endothelial cells,
which could originate both from the injured tissue or migrate from
outside of the injured organ through the bloodstream. (4) Stromal
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