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affecting neuronal responses to injury in autocrine and paracrine manners
(
Hans et al., 1999; Kirsch, Schneider, Lee, & Hofmann, 1998; Leibinger
et al., 2009; Schwartz et al., 1994; Subang & Richardson, 2001
).
Cytokines are also retrogradely transported by axons to their cell bodies
after injury (
Abe & Cavalli, 2008; Curtis et al., 1994; Kirsch, Terheggen,
& Hofmann, 2003; Thompson, Vernallis, Heath, & Priestley, 1997;
Zigmond & Sun, 1997
). In the PNS, such injury responses seem to alter
neuronal gene expression and facilitate initiation of axon regrowth
following axotomy. The most extensively studied cytokines in the context
of axon regeneration are those that belong to the IL6 family or the
glycoprotein 130 (gp130) family. This family includes, among other
cytokines, IL-6, IL-11, oncostatin M, and cardiotrophin-1 along with LIF
and CNTF (
Taga & Kishimoto, 1997
). Cytokine binding leads to
dimerization of gp130 (
Taga et al., 1989
) and phosphorylation of receptor-
associated JAK. This, in turn, phosphorylates causes the dimerization of
STAT3, allowing nuclear translocation and the transcription of target genes
(
Fig. 7.2
). STAT3 is the major signaling pathway in this context, but
gp130 also activates other signaling pathways including extracellular-
regulated kinase (ERK) and PI3K (
Heinrich et al., 2003
). Several studies
have demonstrated that neuropoietic cytokine activation of gp130
facilitates axon regeneration in the PNS neurons. This effect seems to be
mediated primarily via downstream activation of the JAK/STAT signaling
pathway (discussed further in
Section 3.3
). IL6 levels increase in DRGs
after nerve injury (
Murphy, Grondin, Altares, & Richardson, 1995
), and
regeneration is impaired in knockout mice with deletion of LIF (
Cafferty
et al., 2001
)orIL6(
Cafferty et al., 2004; Galiano et al., 2001
). Genetic
deletion of gp130 in sympathetic neurons inhibits the enhancement of
axon growth occurring after conditioning lesion (
Hyatt Sachs, Rohrer, &
Zigmond, 2010
). Overall, these studies indicate that injury-induced
upregulation of cytokines may act as an injury signal in the activation of
the regenerative program in peripheral neurons.
3.2. SOCS3 inhibits CNTF effects
One of the gp130 family of cytokines most extensively studied for axon
regeneration is CNTF, a polypeptide hormone originally characterized as a
potent survival factor for chick ciliary neurons (
Adler, Landa, Manthorpe,
& Varon, 1979; Barbin, Manthorpe, & Varon, 1984; Lin et al., 1989
).
CNTF uses a multimeric receptor composed of the gp130 signal-
transducing protein associated with LIF receptor and the CNTF binding
