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with poor prognosis
[59-62]
. Such apparently contradictory correlations should be
interpreted with caution, as the TBI population is notoriously heterogeneous because
of individual differences in patterns of brain damage, number of patients recruited in
the studies, and the selection of values used for statistical analyses.
In animal models of TBI, IL-6 has been detected mostly in brain tissue as early as
1 hour, peaking between 2 and 8 hours postinjury, though in some studies the cytokine
was elevated between 1 and 6 days posttrauma
[57,63-65]
. In numerous laboratories,
IL-6 has been detected after focal TBI in the CSF
[65]
, in brain tissue at the mRNA/
protein level
[63,64,66,67]
, or in microdialysates
[68,69]
. After diffuse TBI, IL-6 was
found to be elevated in CSF as well as detectable on brain sections by immunohis-
tochemistry and
in situ
hybridization
[57]
.
In vitro
, IL-6 seems to possess multiple
beneficial properties, as it inhibits glutamate excitotoxicity and TNF production, and
induces IL-1 receptor antagonist (IL-1ra), which counteracts the detrimental effects
of IL-1. IL-6 also promotes angiogenesis and astrocyte growth, thereby aiding tissue
repair. In addition, we have previously shown that IL-6 has the ability to stimulate syn-
thesis of the neurotrophic factor nerve growth factor (NGF) by cultured astrocytes, in
response to incubation with IL-6-containing human CSF collected from TBI patients
[53]
. Experiments on IL-6 knockout mice have shown that astrogliosis, together
with the recruitment of macrophages, is reduced after cryolesion coinciding with
enhanced oxidative stress and neuronal cell death
[70,71]
. To the contrary, our labora-
tory found that IL-6 deficiency had no effects on outcome following focal TBI
[72]
.
Alternatively, astrocyte-driven overexpression of IL-6 conferred neuroprotection after
TBI, whereas other studies demonstrate that uninjured IL-6 transgenic mice exhibit
spontaneous neurodegeneration
[73,74]
. Collectively, these findings only add to the
controversy created by studies using different models of brain damage (cryolesion
versus focal cortical contusion) and genetic manipulation of cytokine expression with
either deletion or overexpression in injured and naïve mice.
Since the early 1990s, the function of TNF after TBI has been the focus of a mul-
titude of studies with various and opposing outcomes
[75]
. TNF is a key initiator
of inflammation capable of inducing a large number of pro- and anti-inflammatory
cytokines and chemokines. Though considered to be the main neurotoxic cytokine
mediating cell death in cultured neurons and oligodendrocytes, the actual role of
this important immune mediator remains obscure. In models of TBI, large number
of studies have shown amelioration of CNS damage following therapeutic blockage
of TNF. The deleterious functions of TNF are mostly mediated by one of the two
receptors (p55), thus implicating TNF in the pathogenesis of neurological diseases
and cell apoptosis. However, the opposing beneficial effects are likely attributable
to the alternative receptor (p75), which seems to be involved in remyelination and
repair. After brain trauma, an early production of TNF was shown at protein and
mRNA levels in brain tissue
[63,64,76-78]
, or protein in rodent and human CSF
and microdialysate
[45,65,79-81]
. However, no changes in TNF expression were
found in a mild diffuse TBI rat model
[82]
, or in our protein and mRNA analysis
following focal brain injury in the mouse
[17,83]
. Lack of TNF expression in our
experiments contradicts previous findings (
Table 10.1
) and may relate to the differ-
ence in TNF expression between mice and rats, as most of the initial studies were
