Biology Reference
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This response is driven by TNF
which amplifies the response by
stimulating other inflammatory cytokines and attracting immune
competent cells into the vicinity of the injury. However, this highly
amplified positive control system could easily spin out of control
unless very tightly regulated. EPO made in and around the locale
of injury has been found to play this major role by limiting the
production of inflammatory cytokines as well as protect cells that
have been exposed to molecular signals that would otherwise acti-
vate self-destructive properties, e.g., apoptosis. The temporal-
spatial aspects of this endogenous protective system is distinctive.
TNF
α
(and probably other proinflammatory cytokines) stimulate
the expression EPO and of a receptor for EPO in the immediate
region surrounding the lesion. However, TNF
α
and EPO are
mutually suppressive of each other's synthesis and biological activi-
ties. Therefore, cells closest to a lesion that express EPOR do not
highly express hypoEPO. At the periphery of the lesion (where
TNF
α
concentrations are lower) hypoEPO is synthesized, but with
a significant time delay. This mismatch between abundant receptor
and limited ligand suggests that exogenous receptor activators
could significantly attenuate damage over that mediated by the
endogenous system.
The first non-hematopoietic activity for EPO was observed for
endothelial cells. Here it was observed that EPO exposure in vitro
stimulated endothelial cells to undergo mitosis and migrate—the
first steps in neoangiogenesis (
11
). Interestingly, the concentration
of EPO that elicited this behavior was observed to be substantially
above that required for erythropoiesis (~2 nM versus 100 pM).
Subsequent work showed that pheochromocytoma (neuronal-like)
cells also expressed a receptor that bound EPO (
12
). Biochemical
analysis showed, however, that this receptor appeared to be differ-
ent, having a molecular weight and was associated with different
proteins than was the homodimeric receptor (EPOR)
2
that medi-
ated erythropoiesis. Further, the affinity of this receptor for EPO
was lower (~16 nM) than for (EPOR)
2
(~100-200 pM). Subsequent
in vivo and in vitro work revealed that the affinity for the EPO
receptor that mediated tissue protection was uniformly lower than
for erythropoiesis. These observations suggested that the EPO
receptor that provides tissue protection is an alternate form of
EPOR.
The existence of an additional EPO receptor raised the possi-
bility that receptor-specific ligands might be developed, as has been
accomplished in many other biological systems characterized by
receptor isoforms. AsialoEPO was clearly not such a ligand.
Although asialoEPO had been functionally shown to preferentially
signal the tissue protective system, this molecule none-the-less
binds to (EPOR)
2
. In fact, with the loss of the negative charged
terminal sialic acids, asialoEPO actually has an increased affinity for
the hematopoietic receptor, and therefore a higher specific activity
α
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