Biology Reference
In-Depth Information
HIF are often viewed as oppositely regulated (for instance, HIF is
activated by hypoxia and antioxidants, NF-kB is activated by hyper-
oxia and inhibited by antioxidants (
9, 10
)). On the other hand, it
has been shown that inflammatory/immune cytokines can activate
HIF (
11
) and it is becoming more and more clear that hypoxia and
inflammation are linked (
12, 13
). It should also be noted that HIF
is activated by a number of infectious pathogens (
14, 15
). While
the relationships between HIF-induced cytokines (mainly EPO
and VEGF) in the context of inflammation are the subject of many
studies, it is not always clear how the tissue-protective activity
might not be exclusive of EPO but is shared by other cytokines.
The broad spectrum of tissue-protective activities of EPO,
demonstrated now by over 500 papers published in the past
10 years, also prompted a number of clinical trials.
Like EPO, G-CSF is also being studied in clinical trials for its
tissue- or neuro-protective effect in a variety of indications (Table
1
).
The protective effects of EPO and G-CSF have led us to
reevaluate the literature on tissue-protective actions of other cytokines.
Some of these works, many focusing on neuroprotection, are sum-
marized in Table
2
. Although this table may not be comprehen-
sive, it can be seen that the largest body of evidence, apart from
EPO that is not listed here, is on G-CSF, GM-CSF, IL-6, and
other cytokines of the IL-6 family (CNTF, LIF, CT-1, IL-11). All
these belong to the family of hematopoietic cytokines (
16, 17
). In
the case of IL-6, there is some interest in the development of a
superagonist (hyper-IL-6) which is a fusion protein containing
IL-6 and IL-6 receptor alpha that show a broad range of neuro-
protective and reparative activities (
18-21
), and has been studied
for its pro-myelinating properties (
21
). Interestingly, other pro-
teins of this structural family have protective activities. Growth
hormone (GH) is protective in various injury models (
22-30
).
Also, Flt3 ligand (Flt3L), which has common structure with
hematopoietic cytokines (
31
) improves recovery after spinal cord
injury in rats (
32
) and has neurotrophic activity in vitro (
33
).
Some of the studies listed above have investigated the mecha-
nism of protective activity. To be precise, in the case of G-CSF and
GM-CSF, the rationale for their use in clinical trials has been mainly
to promote repair through mobilization of stem cells. This is also
an effect that may be important for the broad tissue-protective
action of EPO (
34
). It should be noted that most of the studies
listed here provide evidence for a direct protective effect, not medi-
ated by immunomodulation as it could happen with some cytok-
ines, for instance IL-13 (
35
). Of note, even IL-10, originally tested
in models of cerebral ischemia on the ground of its anti-in flammatory
activity mediated by inhibition of TNF synthesis, was found to be
directly neuroprotective in vitro (
36, 37
). The same holds true for
EPO that, while inhibiting the induction of inflammatory cytokines
in experimental stroke (
7
), also protects directly primary neurons
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