Biology Reference
In-Depth Information
Cytokines
Elevation in
ROS level
gp130
gp130
PP
JAK
JAK
STAT3
Alteration in
metabolic
function
P
P
P
P
Upregulated electron
transport chain
Axonal TFs
transported
retrogradely
as injury
signals
SOCS3
STAT3
P
Transcriptional
regulation of
RAGs
Promoter
GENEs
SOCS
3
RAGs
For example, P21/Cip1/Waf1, the small proline rich protein 1a
SPRR1A) and the IFN regulatory factor 1 (IRF1)
Facilitation of
axon growth
Figure 7.2 SOCS3 pathway and axon growth inhibition. Cytokines of gp130 family,
including IL6, LIF, and CNTF, are upregulated after injury. Cytokine binding leading
to activation of gp130 and coreceptors results in transphosphorylation at receptor in-
tracellular domains, which leads to JAK recruitment and JAK phosphorylation. STAT3 is
subsequently recruited to the activated peripheral complexes by phosphorylated-JAK.
Upon JAK phosphorylation, STAT3 is phophorylated (activated), dimmerizes, translo-
cates into the nuclei, and recruited to DNA binding sites of many genes including
regeneration-associated genes (RAG) including the cell cycle inhibitor P21/Cip1/Waf1,
the small proline rich protein 1a (SPRR1A), and the IFN regulatory factor 1 (IRF1). SOCS3
is a direct target of STAT3, acts as a feedback mechanism, and inhibits JAK-STAT signal-
ing in the cytoplasm. Activated STAT3 is also found in mitochondria, which were shown
to contribute to neurite outgrowth in response to nerve growth factor. STAT3 is also
retrogradely transported from the lesioned axon to the cell body, possibly acting as
a signal to initiate neuronal injury responses.
and neurite outgrowth of DRG neurons. Further, inhibition of endogenous
SOCS3 through overexpression of a dominant negative (DN) mutant
SOCS3 stimulates neurite outgrowth (
Miao et al., 2006
).
3.1. Glycoprotein 130 family of cytokines triggers axon
regeneration
Axon injury in the PNS and CNS is followed by upregulation of cytokines at
the lesion site and around the cell body. Both neurons and glial cells are
responsible for increasing the production and release of cytokines, thereby
