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although IL-6 can increase axonal growth in vitro and in vivo (
121,
122
), IL-6 knockout mice show normal axon regeneration (
122
)
indicating that additional investigations are warranted to further
understand the effect of gp130 signaling on axonal regeneration.
In addition to the effect of the IL-6-gp130 signaling through
the activation of AKT and SOCS3, this signaling imposes an effect
on sensory neuronal growth upon activation of STAT3. In primary
sensory neurons, transduction and activation of STAT3 enhanced
neurite growth, transduction with SOCS3 reduced neurite out-
growth, and transduction with mutant SOCS3 enhanced neurite
growth (
123
).
10
Kidney Regeneration and IL6-gp130 Signaling
There is growing evidence that neonephrogenesis—kidney
regeneration—is not only a feature of fish, but also of mammals
(
124
). There is also evidence suggesting that there exists a multi-
potent stem cell in the kidney and that the adult mammal kidney
could regenerate. IL-6 was previously shown to induce kidney
tubular regeneration in rats (
125
) and it is also produced by the
tubular epithelium in the kidney (
126
). Based on the cumulating
data on the role of IL6 trans-signaling in tissue regeneration and
repair, we assessed the role of hyper-IL6 in kidney protection and
regeneration. The administration of hyper-IL6 to mice before
inducing kidney injury prevented severe acute kidney injury and
death of animals (
66
). This effect was mediated through STAT3
activation and subsequent upregulation of genes responsible for
tissue protection as heme oxygenase 1. It is becoming apparent
that also the signaling through ERK and AKT, both downstream
to gp130, are essential for the protection and regeneration fol-
lowing acute kidney injury (
127
).
11
Outlook: Possible Therapeutic Applications
The biology of IL-6 acting via membrane-bound and soluble
receptors is complex. As indicated above, different physiologic sig-
nals are mediated by these two pathways called classic- and trans-
signaling. The activation of gp130 is central to all our phenotypic
observations in regeneration, self-renewal, survival, and anti-apoptosis.
Investigating the structural molecular interactions of gp130 with its
family of cytokine receptors (
128
), e.g., OSM or CNTF and the
analysis of tissue specific gp130 KO mice (
129
) had taught us that
there could be redundancy of ligands, e.g., OSM or CT-1 and in
downstream mediators—STAT3, AKT, and ERK1/2. This overlap
could explain some of the controversies in the field, while different
groups propose a protective vs. a regenerative potential to the
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