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Departments of
*
Clinical Neurosciences and
Oncology, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada; and
Laboratory of Molecular Endocrinology and Department of Anatomy and Physiology, Laval University, Quebec, Canada
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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become significantly elevated within the CNS parenchyma by 3 h
after a brain stab wound injury, and are localized to the lesion site
(4). The source of inflammatory cytokines in the CNS following trauma remains unresolved. Infiltrating leukocytes are obvious candidates, but the CNS is unlike other organs in that the influx of leukocytes is delayed in response to an acute insult. Thus, neutrophils do not infiltrate appreciably until about 6 h after injury, whereas T cells and monocytes appear between 12 to 24 h or later (5, 6, 7, 8, 9). These results suggest that the CNS mounts an early and intrinsic inflammatory response upon injury, before leukocyte infiltration occurs. The origin of the early increase in inflammatory cytokines within the CNS following trauma remains unresolved, although microglia have been suggested as possible sources (2, 3).
Another hallmark of CNS injury is the posttrauma transient expression of neurotrophic factors around the lesion site. Early studies by Nieto-Sampedro et al. (10) showed that extracts collected from sites of brain injury promoted the survival of sympathetic, parasympathetic, and sensory neurons in culture. More recent work has identified these factors to include nerve growth factor (NGF)3 (11), ciliary neurotrophic factor (CNTF) (12, 13), basic fibroblast growth factor (13), and insulin-like growth factor-1 (14). If this transient release of trophic factors could be prolonged, the ability of the CNS to recover from injury may be improved.
An important step to being able to manipulate the duration and magnitude of neurotrophic factor activity is to identify the molecular mediators involved in their production. In this regard, the relationship between inflammatory cytokines and neurotrophic factors, given their similar spatial expression following injury, may be critical. In vitro, a number of reports have shown inflammatory cytokines to influence the induction of neurotrophic factor production, with much emphasis placed on the induction of NGF by IL-1 (reviewed in Ref. 15). This work has also been carried over to an in vivo context in which exogenous administration of IL-1 into the brain has resulted in the up-regulation of NGF (16, 17).
In contrast, very little work has been done to examine whether inflammatory cytokines affect CNTF production. CNTF is of particular interest because, in addition to being a survival factor for various neuronal populations, it has potent effects on cells of the oligodendroglial lineage (reviewed in Ref. 18). CNTF has been shown to be an important maturation factor for oligodendrocytes, to promote their synthesis of myelin proteins (19, 20), and to protect oligodendrocytes from apoptotic death induced by several agents (19, 21). Thus, the regulation of CNTF expression in the CNS following injury may be particularly important for attenuating neuronal and oligodendrocyte death.
The principal aims of this study were to elucidate the earliest period posttrauma in which elevation of inflammatory cytokines occurs, to define the cell type responsible for the initial elevation of cytokines, and to establish if a causal relationship exists in vivo between the elevation of inflammatory cytokines and CNTF following CNS corticectomy trauma.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Adult retired female breeders (4–6 mo) of the CD1 strain
(Charles River, Montreal, Canada), IL-1ß-/-
mice (129Sv/C57BL6, back-crossed for three generations with the B10RIII
strain as previously described) (22), and the B10RIII
genetic controls (The Jackson Laboratory, Bar Harbor, ME) were housed
on a 12-h light/dark cycle with ad libitum access to food and water.
All experimental procedures were approved by the institution’s animal
care committee and were in accordance with the guidelines instituted by
the Canadian Council of Animal Care. CD1 mice were used in the
experiments of
Figs. 1–6
, whereas the IL-1ß-deficient mice and their
wild-type controls were used in the experiments of Figs. 7 and 8.
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Corticectomy injury, in which a 12–15 mm3
volume of parietal-occipital cortex is removed by gentle aspiration,
was used as a model of CNS trauma (Fig. 1
a). This previously
established model is advantageous for the local delivery of test
compounds to the injury site and mimics similar procedures performed by
neurosurgeons for the resection of brain tumors, eplileptic foci, etc.
(23). Briefly, animals were anesthetized with ketamine
(200 mg/kg i.p.) and xylazine (10 mg/kg i.p.) and immobilized in a
stereotaxic frame. Although anesthetics may have protective or
detrimental properties on the parameters analyzed in this manuscript,
it should be noted that all experimental groups were subjected to the
same anesthesia regimen, thus controlling for unknown factors that may
be introduced in this regard.
A midline incision was made, followed by a unilateral circular (2 mm
diameter) craniectomy over the left hemisphere, 1 mm lateral of the
midline suture, and exactly midway between the lambda and bregma
sutures. Precise stereotaxic coordinates were not used given that the
size of the inflicted wound was comparatively large, in accordance with
previous descriptions (23). Following removal of the dura
mater, corticectomy was performed by aspiration of the cortex just down
to the dorsal aspect of the corpus callosum. Recombinant murine IL-1ß
(50, 200, or 1000 U) (R&D Systems, Minneapolis, MN), recombinant human
IL-1 receptor antagonist (IL-1ra; 50 µg/ml) (Amgen, Thousand Oaks,
CA), or a saline control were administered locally into the lesion site
by means of a piece of absorbent gelatin sponge (Gelfoam, Upjohn,
Kalamazoo, MI). Gelfoam was cut to 
1 mm3
dimensions, soaked in a 10 µl volume of the test compound, and
applied directly over the corticectomy site for the duration of the
experiment, as detailed previously (23). All animals were
sacrificed by cervical dislocation.
RT-PCR
The levels of transcripts encoding inflammatory cytokines
IL-1, IL-1ß, and TNF-, as well as CNTF and GAPDH, were
determined by semiquantitative RT-PCR. Total RNA was isolated from
tissue resected from around the lesion site (Fig. 1a) using
the TRIzol reagent (Life Technologies, Burlington, Ontario). Because
the volume of the inflicted tissue ranged from 12 to 15
mm3, care was taken to dissect a rim of tissue
measuring 1 mm encircling the lesion cavity. As an indication that
comparable amounts of tissue were resected for analyses, the total RNA
extracted from all samples was similar. Four samples were collected for
each set of controls and various experimental time points. RNA (0.5
µg) was reverse-transcribed and amplified in a single-step process,
using oligonucleotide primers designed for murine IL-1
(5'-AAGTTTGTCATGAATGATTCCCTC-3', 3'TGAGTAGTGTCCATCACTCTG-5');
IL-1ß (5'-CAGGATGAGGACATGAGCACC-3', 3'-CACCTCAAACTCAGACGTCTC-5');
TNF- (5'-ATGAGCACAGAAAGCATGATC-3', 3'-TTAAGCTCACTGTTCGGACAT-5');
and GAPDH (5'-CGGAGTCAACGGATTTGGTCGTAT3',
3'-CAGAAGTGGTGGTACCTCTTCCGA-5'), previously described in detail
(4), as well as CNTF (5'-GGCTAGCAAGGAAGATTCGT-3',
3'-AATGGCATGGAAGGTTCCCT-5') (24). All primers were
purchased from Life Technologies. The number of cycles was
predetermined to be in the linear range of amplification for IL-1,
IL-1ß, TNF-, and CNTF (35 cycles) and GAPDH (25 cycles). cDNA
products were electrophoresed on 1.5% agarose gels and visualized with
ethidium bromide incorporation under UV light. NIH Image Analysis
software was used to quantify the size of each cDNA product, which was
then expressed as a ratio to the mean size of the cDNA products of
unoperated controls. GAPDH housekeeping gene was used as an internal
control to demonstrate that equivalent amounts of RNA were loaded per
sample for all samples. Statistical analysis was performed using ANOVA
and Bonferroni posttest.
In situ hybridization (ISH)
Three and 24 h after corticectomy, animals were deeply
anesthetized and then transcardially perfused with 0.9% cold saline,
followed by 4% paraformaldehyde in 0.1 M borax buffer (pH 9.5 at
4°C). Brains were removed, postfixed for 2–8 days, and then placed
in a solution containing 10% sucrose diluted in 4%
paraformaldehyde-borax buffer overnight at 4°C. The frozen brains
were mounted on a microtome (Reichert-Jung, Cambridge Instruments,
Deerfield, IL) and cut into 20-µm coronal sections from the olfactory
bulb to the end of the medulla. The sections were collected in a cold
cryoprotectant solution (0.05 M sodium phosphate buffer (pH 7.3), 30%
ethylene glycol, and 20% glycerol) and stored at -20°C.
Hybridization histochemical localization of IL-1, IL-1ß, and
TNF- transcripts was conducted on every sixth section of the whole
rostro-caudal extent of each brain as described previously
(25). The sections were exposed at 4°C to x-ray films
(Kodak, Rochester, NY) for 24 h, dipped into NTB2 nuclear emulsion
(Kodak; diluted 1:1 with distilled water), and exposed for 8–15 days
before being developed and counterstained with thionin (0.25%).
The IL-1 and -1ß cRNA probes were generated from the full-length
mouse IL-1 and -1ß cDNAs (Dr. P. Gray, Genentech, South San
Francisco, CA) subcloned into PCR II (Invitrogen, Carlsbad, CA) and
linearized with XhoI (IL-1 antisense, IL-1ß sense),
KpnI (IL-1ß antisense), or BamHI (IL-1
sense). The 1.3-kb mouse TNF cDNA (Dr. Dr. D. Radzioch, Laval
University, Quebec, Canada) was subcloned into pBluescript
SKII+ and linearized with BamHI and
PstI for the sense and antisense riboprobes, respectively.
Radioactive cRNA copies were synthesized by incubating 250 ng of
linearized plasmid in 6 mM MgCl2, 40 mM Tris (pH
7.5), 2 mM spermidine, 10 mM DTT, 0.2 mM ATP/GTP/CTP,
[-35S]UTP, and 40 U RNAsin (Promega,
Madison, WI), and 20 U of T7 (IL-1 sense, IL-1ß antisense, TNF-
sense), SP6 (IL-1 antisense, IL-1ß sense), or T3 (TNF-
antisense) RNA polymerase for 60 min at 37°C. Unincorporated
nucleotides were removed using the ammonium-acetate precipitation
method; 100 µl of DNase solution (1 µl DNase, 5 µl of 5 mg/ml
tRNA, and 94 µl of 10 mM Tris/10 mM MgCl2) was
added, and 10 min later an extraction was accomplished using a
phenol-chloroform solution. The cRNA was precipitated with 80 µl of 5
M ammonium acetate and 500 µl of 100% ethanol for 20 min on dry ice.
The pellet was washed with ethanol, dried, and resuspended in 100 µl
of 10 mM Tris/1 mM EDTA (pH 8.0). A concentration of
107 cpm probe was mixed into 1 ml of
hybridization solution (500 µl formamide, 60 µl of 5 M NaCl, 10
µl of 1 M Tris (pH 8.0), 2 µl of 0.5 M EDTA (pH 8.0), 50 µl of
20x Denhart’s solution, 200 µl of 50% dextran sulfate, 50 µl of
10 mg/ml tRNA, 10 µl of 1 M DTT, and 118 µl Depc water minus volume
of probe used). This solution was mixed and heated for 5 min at 65°C
before being spotted on slides.
Combined immunocytochemistry (ICC) and ISH
ICC was combined with ISH to determine the type(s) of cells that express IL-1ß transcript in the parenchymal brain at the edge of the cortical lesion. Microglia were labeled with an Ab against ionized calcium binding adapter molecule 1 (Iba1), previously described in detail to be specific for microglial cells (26), and astrocytes were labeled with an Ab against glial fibrillary acidic protein (GFAP). Every sixth brain section was processed by the avidin-biotin method with peroxidase as a substrate. Briefly, slices were washed in sterile Depc-treated 50 mM potassium PBS (KPBS) and incubated at room temperature with either Iba1 (rabbit anti-rat Iba1; generously provided by Dr. Y. Imai, National Institute of Neuroscience, Kodaira, Tokyo, Japan) or GFAP (rabbit anti-cow GFAP; Chemicon International, Temecula, CA) Ab diluted in sterile KPBS, 0.4% Triton X-100, 0.25% heparin sodium salt USP (ICN Biomedicals, Aurora, OH), and 1% BSA (fraction V; Sigma, St. Louis, MO). Two hours after incubation with the primary Ab, sections were rinsed in sterile KPBS and incubated with biotinylated secondary Abs (Vector Laboratories, CA) for 60 min. Sections were then rinsed with KPBS and incubated at room temperature for 60 min with an avidin-biotin-peroxidase complex (Vectastain ABC elite kit, Vector Laboratories). After several rinses in sterile KPBS, the brain slices were reacted in 0.05% diaminobenzidine (DAB) and 0.003% hydrogen peroxide (H2O2).
Thereafter, sections were rinsed in sterile KPBS, immediately mounted onto gelatin- and poly-L-lysine-coated slides, dessicated under vacuum for 30 min, fixed in 4% paraformaldehyde for 20 min, and digested by proteinase K (10 µg/ml in 100 mM tris HCl (pH 8.0) and 50 mM EDTA (pH 8.0)) at 37°C for 25 min. Prehybridization, hybridization, and posthybridization steps were performed according to the above description with the difference of dehydration (alcohol 50, 70, 95, 100%), which was shortened to avoid decoloration of immunoreactive cells (brown staining). After being dried for 2 h under vacuum, sections were exposed overnight at 4°C to x-ray film (Kodak), defatted in xylene, and dipped in NTB2 nuclear emulsion (Kodak; diluted 1:1 with distilled water). Slides were exposed for 14 days, developed in D19 developer (Kodak) for 3.5 min at 15°C, and fixed in rapid fixer (Kodak) for 5 min. Sections were then rinsed in running distilled water for 1–2 h, rapidly dehydrated through graded concentrations of alcohol, cleared in xylene, and coverslipped with DPX. The presence of IL-1ß transcript was detected by the agglomeration of silver grains in perikarya, whereas Iba1 immunoreactivity within the cell cytoplasm and ramifications was indicated by a brown homogenous coloration. Determination of the double-labeled cells was performed visually for each cell exhibiting clear brown cytoplasm and a number of silver grains within the cell body, delineating convincing hybridized message.
Hematoxylin and eosin staining
Animals were anesthetized and transcardially perfused with 0.9% saline followed by 4% paraformaldehyde in 0.1 M phosphate buffer. Brains were removed, postfixed in 4% paraformaldehyde, and then embedded in paraffin and cut into 4–6 µm sections. Sections were heated for 1 h at 60°C, deparaffinized in xylene, and rehydrated through a graded series of alcohol to water and PBS. Sections were then stained with hematoxylin and eosin, dehydrated through a graded series of alcohol and xylene, and coverslipped with Permount.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Brain tissues from uninjured adult CD1 mice express low to
undetectable levels of cytokine transcripts when measured by the highly
sensitive method of RT-PCR (Fig. 1b). In contrast,
inflammatory cytokine transcripts are rapidly up-regulated around the
lesion site following a corticectomy injury (Fig. 1b). When
compared with unoperated controls, mRNA encoding IL-1ß was
significantly elevated within 15 min after injury, followed by IL-1
and TNF- which increased by 1 h (Fig. 2a). Levels of all three
proinflammatory cytokines peaked at 3 h following injury. The
magnitude of increase of TNF- is less than that of IL-1ß or
IL-1 and is related to the higher basal level of TNF- in normal
uninjured animals (see Fig. 1b). By ISH, IL-1, IL-1ß,
and TNF- are localized to cells in the brain parenchyma around the
lesion site at 3 and 24 h postinjury (Fig. 3).
The relationship of the up-regulation of cytokines to that of CNTF mRNA
was examined (Fig. 2b), and it was discovered that
CNTF transcripts become significantly elevated first at 1 h
and peaked by 12 h postinjury, which follows the up-regulation of
IL-1ß.
The up-regulation of IL-1ß following injury is a CNS intrinsic response
To determine whether the observed up-regulation of IL-1ß was due
to the infiltration of neutrophils, known to be one of the earliest
cells to respond to injury, tissues were stained with hematoxylin and
eosin to visualize polymorphic nuclei. Polymorphonuclear cells were
only observed in the CNS by 1 and 2 days after injury (Fig. 4) and not at 1 and 3 h, the
earliest time points that we examined and which correspond to peak
elevation of IL-1ß transcript. Because monocytes, which are also
sources of IL-1ß, do not infiltrate the CNS until much later, the
initial production of cytokines appears to be a CNS intrinsic
response.
Combined ISH and ICC revealed the cellular source of IL-1ß to be the
CNS resident macrophage, the microglia (Fig. 5). Cells positive for IL-1ß mRNA
overlapped entirely with Iba1-positive microglia in the parenchymal
tissue surrounding the lesion site. However, we noted that not all
Iba1-positive microglia express IL-1ß transcripts (Fig. 5),
suggesting heterogeneity in the response of microglia to injury.
GFAP-immunoreactive cells were not present in regions depicting
hybridization message for the proinflammatory cytokine, which does not
support astrocytes as a potential source of IL-1ß during the rapid
inflammatory response that takes place after corticectomy (results not
shown).
IL-1ra blocks the up-regulation of CNTF
Given the very early increase and peak of IL-1ß elevation before
the increase of CNTF transcripts, we examined if a relationship of
IL-1ß affecting CNTF could be evidenced. This was first approached by
determining the effect of blocking the actions of IL-1ß around the
lesion site of CD1 mice, considering that this cytokine has been shown
by ISH to be localized immediately around the area of injury (Fig. 3).
Direct application of IL-1ra was made into the corticectomy site
through an absorbent gelatin sponge, gelfoam, which overlaid the lesion
cavity. We have previously described this technique to apply drugs
locally to the injury site and have shown that the application of
IL-10, a cytokine synthesis inhibitor, attenuated the extent of
astrogliosis and inflammatory cytokine production (23).
The application of IL-1ra suppressed the up-regulation of CNTF at
12 h postcorticectomy (Fig. 6), the
time point corresponding to peak CNTF transcript elevation in normal
corticectomized mice.
IL-1ß-/- mice fail to up-regulate CNTF
Mice genetically deficient for IL-1ß were subjected to a
corticectomy insult to address their capacity to generate
proinflammatory cytokines and CNTF. IL-1ß-/-
mice did not express IL-1ß or IL-1 cytokine transcripts under
basal conditions or following corticectomy injury (data not shown) but
did express TNF- which is elevated upon injury, confirming the
competence of these animals to mount an inflammatory response to brain
injury (Fig. 7a). A subsequent
examination of CNTF mRNA after corticectomy in
IL-1ß-/- animals (Fig. 7a)
revealed no elevation of this trophic factor at time points
corresponding to elevated and peak increase in wild-type animals (Fig. 7b). Basal levels of CNTF transcripts in uninjured animals
were equivalent in the IL-1ß mutants and their genetic controls (Fig. 7c).
Rescue of CNTF mRNA elevation in IL-1ß-/- mice
If IL-1ß is required for CNTF production in CNS trauma, then the
phenotype of lack of CNTF elevation in
IL-1ß-/- mice should be restored by the
application of exogenous IL-1ß. Indeed, when IL-1ß was introduced
into the lesion site by gelfoam, an elevation of CNTF was observed at
12 h postcorticectomy, a time point corresponding to peak CNTF
elevation in normal, corticectomized mice (Fig. 8). Collectively, the data strongly
support the requirement for IL-1ß in the up-regulation of CNTF
following traumatic brain injury.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, and TNF- occur
during a period where no leukocytes are apparent. This suggests a CNS
intrinsic source and is confirmed by the localization of IL-1ß
transcript to microglia alone, at least at 3 h following injury.
That microglia are the sole sources of IL-1ß early on in trauma
fulfills the prediction of Kreutzberg (30) that microglia
are the sensors of CNS pathology.
As mentioned earlier, several other studies have also reported an early
rise in the inflammatory cytokines IL-1ß and TNF- following CNS
trauma (2, 3) or in response to excitotoxic damage
(31). Our finding that IL-1ß transcripts increase by 15
min following corticectomy is the earliest that anyone has observed in
CNS trauma.
Neurotrophic factors are produced following CNS injury, but the
mechanisms that regulate their elevation remain unresolved. In the
peripheral nervous system, it has been shown that the lesion-mediated
increase in NGF is primarily regulated by the production of IL-1 by
activated macrophages (32). In the CNS, studies have
similarly implicated a role for IL-1ß in the induction of NGF
expression by astrocytes in vitro and in vivo (16, 33).
The role of IL-1 in the production of other trophic factors, such as
CNTF, is largely unknown, although IFN-
(34) as well as
IL-1ß and TNF- (35) can up-regulate CNTF production
in astroglial cultures. In this paper we have addressed whether IL-1ß
mediates the production of CNTF in vivo following CNS trauma. A
temporal profile for proinflammatory cytokines and CNTF transcript
elevation was established using the corticectomy model of injury. The
increase in CNTF temporally follows the increase in IL-1ß, which is
suggestive of a causative role for IL-1ß in the up-regulation of
CNTF. We confirmed such an inferred relationship by showing that
blocking the activity of IL-1ß with its receptor antagonist
attenuated the production of CNTF, and furthermore, that CNTF elevation
was inhibited in IL-1ß-/- animals.
Importantly, the application of exogenous IL-1ß into the injury site
of IL-1ß-/- mice was able to rescue the
phenotype of lack of CNTF elevation in these animals. Taken together,
these findings show for the first time a requirement for IL-1ß in the
production of CNTF following CNS trauma. Thus, the CNS-initiated
IL-1ß increase serves to attempt preservation of the integrity of the
CNS by producing factors that aid the survival of both neurons and
resident glial cells such as the oligodendrocyte.
We are currently investigating the mechanisms by which IL-1ß
regulates CNTF production. It is possible that this occurs through the
induction of the transcription factor NF-
B or AP-1. NF-B and AP-1
consensus sequences have been reported in the CNTF promoter
(34), and many biological effects of IL-1 are known to
occur through NF-B and AP-1-mediated mechanisms (36).
However, other possibilities exist, since an elevation of TNF- but
not CNTF is observed in the IL-1ß-/- mice
(Fig. 7a), and TNF- can also induce the activation of
NF-B or AP-1 transcription factors.
It is noteworthy that the IL-1ß-/- mice did
not express IL-1 following corticectomy, since IL-1 and IL-1ß
are located on separate genes in the mouse. The finding that TNF- is
promptly elevated in the IL-1ß-deficient mice supports that the
failure of IL-1 elevation is not indicative of an inability of these
animals to mediate an inflammatory response within the CNS. A recent
study examining IL-1ß-/- and
IL-1-/- mice has shown that an IL-1ß
deficiency abrogated IL-1 expression, as well as IL-1ß, but not
vice versa, while TNF- expression level was not affected in either
case (37). These authors suggest that the expression of
IL-1, but not TNF-, is mostly dependent on the expression of
IL-1ß; our current findings support such a hypothesis. Furthermore,
our results indicate that TNF- is not adequate to elevate CNTF in
the brain parenchyma following injury, at least within the time points
studied.
The cellular source of production of trophic factors postinjury is an area of interest. Although it is clear that the microglia are the early source of IL-1ß, we were unsuccessful in our attempts to identify the source of CNTF. Nonetheless, the most likely source of CNTF up-regulation following traumatic CNS injury is the astrocytes, since CNTF has been localized to astrocytes in the normal brain (38, 39). Furthermore, the up-regulation of CNTF following CNS trauma has been noted to occur in reactive astrocytes around the lesion site (12, 13, 39, 40).
It remains controversial as to whether inflammation in the injured CNS
serves a beneficial or detrimental purpose (reviewed in Refs.
15 and 41). A number of studies have observed
that TNF- produces apoptotic death to oligodendrocytes and neurons
(19, 21), and some reports have also implicated IL-1ß in
the mediation of neuronal death, particularly following ischemic and
excitotoxic brain injury (42, 43, 44). Inflammation following
CNS trauma would therefore be detrimental in the context of potential
injury to neurons and oligodendrocytes, and reports of the
correspondence of the number of macrophages/microglia with the amount
of tissue damage at each level of the spinal cord in contusion injury
(e.g., Carlson et al. (45)) would be consistent with such
a hypothesis. In contrast, other reports indicate that inflammation may
be beneficial to recovery. In earlier work, David et al.
(46) showed that the nonpermissive nature of the rat optic
nerve could support neurite extension from dorsal root ganglia if
treated with macrophages isolated from the injured brain. Several
reports demonstrate that the application of inflammatory cytokines to
lesioned areas was neuroprotective or promoted the regeneration of
axons (47, 48). More recently, the transplant of cultured
microglial cells (49) or monocytes (50) into
the injured spinal cord led to enhanced neurite outgrowth. To
complicate matters further, the role of inflammation in the CNS may be
structure or region specific. A recent study observed that IL-1ra
infusion into the striatum reduced excitotoxicity-induced neuronal
damage, but failed to protect neurons in the cortex (51).
Finally, inflammation in the CNS likely leads to the evolution of
astrocyte reactivity (23, 52), and the multiple beneficial
or detrimental effects of astrogliosis (15) will have to
be taken into consideration. The results here of IL-1ß regulating
CNTF clearly suggest the potential of inflammation in the injured CNS
to have neurotrophic potential.
We conclude that an acute trauma to the CNS initiates the microglial production of IL-1ß, and this is required to up-regulate the neurotrophic factor CNTF. This novel observation invites important future directions, including the role that IL-1 plays in the regulation of other neurotrophic factors following injury such as brain-derived neurotrophic factor, glial-derived neurotrophic factor, and basic fibroblast growth factor. Also of interest, and currently a focus of this laboratory, is whether IL-1ß levels can be used to manipulate the production of CNTF to enhance oligodendrocyte survival and remyelination. Resolving the neurotrophic potential of CNS inflammation will have impact on the recovery of the CNS to injury.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. V. Wee Yong, Departments of Clinical Neurosciences and Oncology, Faculty of Medicine, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada.
3 Abbreviations used in this paper: NGF, nerve growth factor; CNTF, ciliary neurotrophic factor; IL-1ra, IL-1 receptor antagonist; ISH, in situ hybridization; ICC, combined immunocytochemistry; GFAP, glial fibrillary acidic protein.
Received for publication April 7, 2000. Accepted for publication June 6, 2000.
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