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Regular Articles |
From the Department of Molecular Genetics,*
Hellenic
Pasteur Institute, Athens, Greece; and the Department of Experimental
Neuropathology,
Institute of Neurology,
University of Vienna, Vienna, Austria
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Abstract |
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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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Considerable evidence has implicated members of the tumor necrosis
factor (TNF) ligand/receptor superfamily, particularly TNF and Fas/Fas
ligand (FasL), in the pathogenesis of MS.12,4,6
TNF and its receptors (TNFRs) are up-regulated in active MS
lesions2,13-15
and levels of TNF in the
cerebrospinal fluid of MS patients correlate with disease
severity.16
The described effects of TNF on
cultured CNS cells such as astrocyte
proliferation,17
microglial proliferation and
reactivity,18
and endothelial cell
activation19
are consistent with an inflammatory
role in the CNS and the induction of immune
reactivity.20,21
Most relevant to a role in
demyelination is increasing evidence that the TNF ligand/receptor
system is involved in triggering oligodendrocyte death. Both the
p55TNFR and the p75TNFR are selectively expressed on oligodendrocytes
located at the edge of active MS lesions15
and
several studies have shown that TNF can kill cultured
oligodendrocytes.6,22-24
However, although a
large body of information supports a potentially major role for TNF
during MS immunopathogenesis and TNF blockade can prevent the
development of EAE,25-28
recent studies showing
that both CNS inflammation and demyelination develop when EAE is
induced in TNF- or TNF/lymphotoxin 
-deficient mice have called into
question the pathogenic potential of TNF along autoimmune-triggered
pathways of inflammation and demyelination.29-33
To determine whether local TNF/TNFR signaling can play a role in MS aetiopathogenesis, particularly in those subtypes of MS in which demyelinating events precede inflammation3,34 and are suggestive of a non-autoantigen-induced mechanism, we have analyzed disease pathology in CNS-expressing TNF transgenic mice35,36 and their backcrosses into p55TNFR-deficient37 or p75TNFR-deficient 38 backgrounds. We show that local production of TNF by CNS glial cells can selectively induce through the p55TNFR oligodendrocyte apoptosis, primary inflammatory demyelination, and the generation of MS-type plaques which have oligodendrogliopathy as a primary pathological feature.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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TNF transgenic lines Tg6074 and TgK21 express murine TNF-globin and glial fibrillary acid protein (GFAP)-human transmembrane TNF-globin transgenes, respectively, specifically in their CNS.35,36 Mice deficient in the p55TNFR (p55-/-), p75TNFR (p75-/-) or TNF (TNF-/-) were generated by homologous recombination in embryonic stem cells and have been described elsewhere.37-39 Animal maintainance and appropriate crosses between these strains were performed under specific pathogen-free conditions in the animal facility of the Hellenic Pasteur Institute.
Histopathological Analyses
Mice were transcardially perfused with ice-cold 4% paraformaldehyde (PFA) in PBS under deep ether anesthesia. The partially dissected brain and whole vertebral column were postfixed by immersion in the same fixative for 3 hours at 4°C and transferred into PBS. Brains and spinal cords were dissected and embedded in paraffin. Sections 3 to 5 µm thick were stained with hematoxylin/eosin, Luxol fast blue/periodic acid-Schiff (LFB/PAS), or Bielschowsky silver stain according to standard procedures.
Immunocytochemistry
Immunohistochemical staining was performed on paraffin sections as described elsewhere.40 Primary antibodies were as follows: rabbit anti-proteolipid protein (PLP) (Serotec, Oxford, UK) (1/1000), mouse anti-2' 3'-cyclic nucleotide-3'-phosphodiesterase (CNPase) (Affinity, Nottingham, UK) (1/900), sheep anti-mouse Ig (Amersham, Little Chalfont, UK) (1/200), rabbit anti-cow GFAP (Dakopatts, Glostrup, Denmark) (1/200), rabbit anti-murine TNF (Genzyme, Cambridge, MA) (1/500), rat anti-mouse F4/80 (Serotec) (1/10), rat anti-mouse Mac-1 (Boehringer-Mannheim, Mannheim, Germany) (1/100), rat anti-human CD3 (Serotec) (1/400), rabbit anti-mouse S-100 (Serva, Heidelberg, Germany) (1/100), and anti-microtubule associated protein-2 (MAP-2) (kindly provided by G. Wiche, Institute of Biochemistry and Molecular Cell Biology, Vienna) (1/400). Lectin staining was performed using GSI-B4 (Sigma, Deisenhofen, Germany). For double immunostaining peroxidase substrates 3',3'-diaminobenzidine (DAB) (Sigma) and 3-amino-9-ethylcarbazole (AEC) (Sigma) were combined with alkaline phosphatase substrate nitroblue tetrazolium (NBT)/brom-chlor-indolyl phosphate (BCIP) (Boehringer Mannheim).
Laser Scanning Confocal Microscopy
For double staining of TNF and CNPase, essentially the same immunocytochemistry procedure was used as for normal light microscopy. Briefly, sections were incubated with both primary antibodies overnight, then incubated with secondary antibodies (rhodamine-conjugated goat anti-mouse (Jackson ImmunoResearch Laboratories, West Grove, PA) and biotinylated sheep anti-rabbit (Amersham)) for 2 hours at room temperature. In a third step, sections were incubated with avidin-conjugated Cy2 (Amersham) for 1 hour at room temperature. After rinsing with PBS, sections were embedded in PBS/glycerol (1:9) with 3% DABCO (Sigma) and placed in a coverslip. Fluorescent preparations were examined using a Carl Zeiss laser scan microscope equipped with an argon laser (488 and 514 nm excitation) and two HeNe lasers (543 and 633 nm excitation) (Carl Zeiss, Jena, Germany). The rhodamine fluorescence (CNPase) was excited with the 543-nm laser. The emitted light was detected on photomultiplier 2 with a 557–640 bandpass filter. Cy2 (TNF) was excited with the 488-nm laser and was detected on photomultiplier 3 using a 515–565 bandpass filter. Scanning with the 543- and 488-nm lasers was performed sequentially. After this, sections made with 543- and 488-nm lasers lying in the same Z plane were merged to produce a single picture. Overlaid pictures were printed with a Sony digital color printer (Cy2 signal green, rhodamine red, co-localization yellow).
In Situ Detection of Nuclear DNA Fragmentation
Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) was performed on paraffin sections as described previously.41 Sections were double-labeled with antibodies to CNPase or GFAP using AEC or DAB for color development. Sections were counterstained with hematoxylin.
In Situ Hybridization of PLP mRNA
Detection of PLP mRNA was performed on brain and spinal cord paraffin sections. Nonisotopic in situ hybridization was performed as described.42 Briefly, 5-µm paraffin sections were dewaxed, pretreated with 10 µg of proteinase K (Sigma) in Tris-buffered solution , pH 7.2, and incubated with digoxigenin-labeled probes specific for PLP. Sections were incubated for 1 hour with alkaline phosphatase-labeled anti-digoxigenin antibody (Boehringer-Mannheim). Substrate was visualized using NBT/BCIP (Boehringer-Mannheim). All sections were double-stained with anti-PLP antibodies as described above with triple APAAP using Fast Red as substrate. Sections were counterstained with hematoxylin.
Electron Microscopic Analyses
Animals were intracardially perfused under deep ether anesthesia with ice-cold 2% PFA, 0.5% glutaraldehyde in 0.1 mol/L phosphate buffer, pH 7.2, for 1 minute followed by ice-cold 3% glutaraldehyde in 0.1 mol/L phosphate buffer for 5 minutes. Brains and spinal columns were removed, immersion-fixed for 24 hours in phosphate-buffered 3% glutaraldehyde, postfixed in 2% osmium tetroxide solution, and subsequently embedded in epoxy resin. Ultrathin sections were cut and counterstained with uranyl acetate and lead citrate.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Transgenic mice which show CNS-specific expression of a murine TNF
transgene (the Tg6074 line) or astrocyte-targeted expression of an
uncleavable transmembrane human TNF mutant (the TgK21 line) have been
reported previously.35,36
TgK21 mice express
human transmembrane TNF under the control of the GFAP promoter region,
and immunocytochemistry on serial spinal cord sections with antibodies
to human TNF and GFAP showed that the TNF transgene is expressed by
GFAP-positive astrocytes.36
To identify the
precise cellular source of murine TNF transgene expression in the CNS
of Tg6074 mice, we have used immunocytochemical techniques to localize
murine TNF immunoreactivity in the CNS. Tissues were taken from
Tg6074TNF-/- double transgenic mice to exclude simultaneous
expression from the endogenous TNF gene. Transgene-positive cells had a
highly ramified appearance and were numerous throughout the brain in
both white and gray matter. Double immunostaining for murine TNF
and markers for mature CNS cell types showed that the TNF transgene is
not expressed in either GFAP-positive astrocytes or F4/80-, Mac-1-, or
GSI-B4 lectin-positive microglia/macrophages (not shown). Single
immunostaining of serial 0.5- to 1-µm paraffin sections for TNF and
S100 (marker for astrocytes and immature glia43)
(Figure 1, A and B)
, MAP-2 (neurons)
(Figure 1, C and D)
, or CNPase (oligodendrocytes) (Figure 1, E–G)
,
demonstrated that TNF immunoreactive cells show low immunoreactivity
for all of these markers when compared to mature cell lineages,
indicating that they are probably CNS glial progenitor cells.
Examination of double-stained sections for TNF and CNPase by confocal
microscopy confirmed that the TNF transgene is expressed by
CNPase-positive cells (Figure 1H)
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To determine the effect of expression of a murine TNF transgene by
resident cells of the CNS on oligodendrocytes and myelin in
vivo, we carried out a detailed histopathological and
ultrastructural analysis of disease in Tg6074 transgenic mice
(Figures 2 and 3
, Tables 1 and 2
).
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, the initial site of transgene expression,
together with widespread microglial activation. Oligodendrocyte
apoptosis developed in the absence of immune infiltration and
blood-brain barrier (BBB) damage in the CNS parenchyma (not shown),
although minimal BBB damage and immune infiltration could be observed
at the meninges.
By 4 weeks of age, early demyelinating events consisting of myelin
swelling and the formation of vacuoles with single fiber degeneration
were observed (Tables 1 and 2)
. This was localized by luxol fast blue
staining or PLP in situ hybridization and
immunocytochemistry for PLP protein in the cerebellar white matter, the
capsula interna (Figure 2, A and B)
, and, to a minor degree, the optic
tracts. Examination of semithin (Figure 3A)
and thin (Figure 3B)
sections by electron microscopy showed myelin swelling within the
periaxonal space of the myelin sheath. Axons within the demyelinating
area appeared intact (Figure 3B)
, showing that TNF-mediated CNS damage
is selective for oligodendrocytes and myelin. Although there was
pronounced inflammation at the brain meninges at this stage, immune
cell infiltration in the brain parenchyma and BBB leakage were minor.
The myelin vacuolation observed in transgenic mice closely resembled
that seen in chronic MS lesions2
and other
demyelinating diseases such as HIV vacuolar myelopathy, which is
associated with massive vacuolation of myelin, axonal preservation, and
in part with infiltration of the periaxonal space by
macrophages/microglia.44
In later lesions (8 to 10 weeks of age), confluent symmetrical plaques
of primary demyelination had developed in all animals tested (Tables 1 and 2)
. Plaques were characterized by loss of both myelin and
oligodendrocytes as shown by double PLP in situ
hybridization and PLP immunocytochemistry (Figure 2G)
, and
oligodendrocyte apoptosis (Figure 2D)
but remyelinating events were not
observed. Ultrastructural analysis showed the presence of
numerous demyelinated axons within the lesions (Figure 3D)
. In the
plaque there were also abundant activated microglia/macrophages
(Figures 2E, 3C, and 3D)
and at the plaque edge several of these cells
contained myelin degradation products (Figure 2F)
demonstrating active
myelin degradation. Moderate axonal damage was evident within the
plaques (Figure 2H)
. Such lesions are accompanied by BBB leakage, some
perivascular lymphocyte infiltration (Figure 2I)
, and astroglial
scarring. All histopathological changes described were restricted to
brain samples where the transgene is abundantly expressed. Such
demyelinating plaques remarkably resemble those of chronic MS
lesions.3,45
Astrocytic Expression of Transmembrane Human TNF Triggers Oligodendrocyte Apoptosis, Primary Demyelination with Axonal Loss, and the Development of Acute MS-Type Lesions
To investigate whether a human transmembrane TNF protein expressed
by astrocytes could also trigger oligodendrocyte and myelin damage
in vivo and thereby assess the importance of p55TNFR
signaling via a contact-dependent manner, we also analyzed CNS tissues
from TgK21 transgenic mice (Figure 4
> and
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had developed in the spinal cord at sites of extreme
inflammation (Figure 4G)
and extensive BBB breakdown (Figure 4F)
.
Myelin loss was accompanied by axonal damage (Figure 4B)
and astrocyte
loss (Figure 4C)
. The presence of numerous phagocytic macrophages
containing PLP positive myelin degradation products in the affected
areas (Figure 4, D and E)
showed that myelin was being phagocytosed by
these cells. As in chronic lesions mentioned above, in situ
hybridization for PLP mRNA showed that PLP-expressing oligodendrocytes
were progressively depleted from demyelinating lesions (not shown).
Combined TUNEL/CNPase immunocytochemistry showed that this loss could
be accounted for at least in part by oligodendrocyte apoptosis (Figure 4, H–J)
. Interestingly, TNF triggered demyelination selectively in CNS
myelin, leaving myelin of the peripheral nervous system intact (Figure 4E)
. The histopathological and ultrastructural characteristics of
spinal cord lesions in TgK21 mice are consistent with those observed in
typical acute MS, where destructive lesions include loss of myelin,
oligodendrocytes, axons, and astrocytes.3,45 The p55TNFR Is Necessary for the Development of TNF-Triggered CNS Inflammation and Primary Demyelination in Transgenic Mice
The present findings that both murine and human TNF can trigger
the development of CNS inflammation, oligodendrocyte apoptosis, and
demyelination in transgenic mice indicate that the p55TNFR plays a
dominant role in the initiation of this phenotype, as human TNF is
unable to signal through the murine p75TNFR.46
To
investigate further the specificity of TNFR signaling in TNF-triggered
CNS pathology, we generated Tg6074 and TgK21 transgenic mice which were
deficient in the p55TNFR and Tg6074 mice which were deficient for the
p75TNFR. All Tg6074p55-/- and TgK21p55-/- mice generated remained
entirely free of clinical symptoms for the study period of 8 months,
while Tg6074p55+/+ and TgK21p55+/+ littermates developed disease as
expected by 4 and 3 weeks of age, respectively. Histopathological
analysis of CNS tissues from Tg6074p55-/-- (n
= 4) and TgK21p55-/- (n = 5) mice aged up to 6
months found no evidence of inflammation or demyelination (Figure 5A)
, showing that the presence of the
p55TNFR is necessary for TNF to trigger these effects. Interestingly,
TgK21p55+/- mice developed much delayed neurological symptoms by the
sixth month of age. At the histological level the CNS from such mice
(n = 2) showed symmetrical, focal demyelinated
plaques at the capsula interna and in the spinal cord (not shown). In
contrast, Tg6074p55+/- mice remained symptom-free during a study
period of 12 months, and such mice (n = 2)
showed no sign of pathology at the histological level. These results
show that the levels of expression of the p55TNFR play a critical role
in determining the pattern and extent of TNF-triggered CNS inflammation
and primary demyelination in vivo. In contrast to
Tg6074p55-/- mice, CNS pathology developed in Tg6074p75-/-
(n = 2) mice with myelin vacuolation,
inflammation and oligodendrocyte apoptosis as in Tg6074p75+/+ controls
(Figure 5, B–E)
, showing that when TNF is overexpressed it can trigger
both inflammation and demyelination through the p55TNFR, even in the
absence of the p75TNFR.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The molecular and cellular mechanisms by which TNF induces CNS inflammation and demyelination in transgenic mice appear to be very specific. The p55TNFR is known to mediate cell death responses (apoptosis) and proliferative effects by differential signaling through intracellular pathways.59-62 Our observation that oligodendrocyte apoptosis is one of the first pathological effects of TNF transgene expression in the CNS suggests that TNF may exert a direct cytotoxic effect on oligodendrocytes. This is substantiated by evidence showing that oligodendrocytes can express TNFRs both in vitro63,64 and in MS lesions15 and by ample evidence that TNF can trigger oligodendrocyte death in vitro.23,6 Furthermore, the recent finding that inhibitors of ICE/CED-3 proteases prevent TNF-mediated oligodendrocyte apoptosis24 show that at least in vitro TNF can trigger intracellular death-signaling pathways in these cells. The observed concomitant inflammatory effects of TNF in the CNS of transgenic mice, including astrocytosis, microgliosis, and endothelial cell activation36 are likely to contribute significantly to progression of the demyelinating process and plaque formation through additional inflammatory mechanisms of myelin and axonal damage. The development of conditional mutant mice in which the p55TNFR can be activated or inactivated in specific CNS cell lineages will allow the individual contributions of different TNF-mediated effects to CNS inflammation and demyelination to be evaluated. Further to an essential role for the p55TNFR in the initiation of TNF-mediated inflammation and demyelination, our studies in transgenic mice have demonstrated that the cellular source of TNF expression within the CNS also plays a critical role in determining whether inflammation and demyelination will develop.36 Our finding that transmembrane human TNF can trigger demyelination when produced by astrocytes but not neurons36 and the observation by others that transmembrane TNF is more effective than soluble TNF in killing oligodendrocytes in vitro65 strongly suggest that TNF-mediated demyelination depends on appropriate cellular contacts between TNF-producing cells and oligodendrocytes or intermediate cells such as microglia/macrophages, and implicate transmembrane TNF as an important effector of oligodendrocyte death in vivo.
Although primary demyelination is the major hallmark of MS, axonal loss
correlates with inflammatory activity and is observed in lesions as
they age.45,66
Similarly, in TNF transgenic mice
axonal damage is not observed as a primary pathogenic effect of TNF
expression suggesting that neurons, in contrast to oligodendrocytes,
may not be direct targets of TNF cytotoxicity in vivo but
are damaged following immune infiltration at sites of
oligodendrocyte/myelin damage. This conclusion is consistent with
several lines of evidence which show that TNF can be
neuroprotective,67-69
probably through the
induction of NF-
B and NF-B-regulated genes in
neurons.68
Our observation that the context of
TNF expression within the CNS determines whether the resulting lesion
will be chronic or acute may therefore relate to the differential
capacity of TNF to trigger parenchymal inflammation and BBB leakage
from different cell sources. TNF induces the development of acute
demyelinating lesions when expressed by astrocytes in TgK21 mice.
Astrocytes form intimate associations with the BBB through their foot
processes and induce BBB properties in CNS endothelial cells
in vitro70
and astrocyte-specific
expression of TNF seems to be crucial for endothelial cell activation
and BBB damage in transgenic mice36
(Akassoglou,
Bauer, Lassmann, Kollias, and Probert,
unpublished observations), suggesting a vigorous inflammatory component
characteristic of acute demyelinating lesions with axonal loss. Taken
together, these results indicate that whereas oligodendrocyte apoptosis
is primary and TNF-dependent, axonal damage is secondary to BBB damage
and immune cell infiltration of the CNS and points to the interesting
possibility that axonal damage in MS, which is largely responsible for
permanent disability, may be limited by treatments that restrict
leukocyte trafficking at the BBB irrespective of disease etiology.
Our results demonstrate that TNF is a potent and selective effector of oligodendrocyte death and primary demyelination in vivo and implicate TNF/p55TNFR signaling as a potentially important mechanism of non-antigen-driven demyelination in MS. In addition, the characterization of the p55TNFR as the dominant receptor in mediating TNF-induced oligodendrocyte cytotoxicity and inflammation in the CNS identifies p55TNF signaling pathways as potentially important targets for cell-specific interventions. The finding that TNF-induced lesions in mice bear remarkable histopathological resemblance to MS lesions, particularly those characterized by primary oligodendrogliopathy, establish TNF transgenic mice as new animal models for MS.
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Acknowledgements |
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Footnotes |
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Supported by European Commission Grants BIO4-CT96–0174 and BIO4-CT96–0077, Hellenic General Secretariat for Research and Technology EPETII/PENED 1995 Program Grant 1629, and European Molecular Biology Organisation Short Term Fellowship ASTF 8543 to KA.
Accepted for publication June 25, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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 P. Jolicoeur, C. Hu, T. W. Mak, J.-C. Martinou, and D. G. Kay Protection against Murine Leukemia Virus-Induced Spongiform Myeloencephalopathy in Mice Overexpressing Bcl-2 but Not in Mice Deficient for Interleukin-6, Inducible Nitric Oxide Synthetase, ICE, Fas, Fas Ligand, or TNF-R1 Genes J. Virol., December 15, 2003; 77(24): 13161 - 13170. [Abstract] [Full Text] [PDF]
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 M Bradl and R Hohlfeld Molecular pathogenesis of neuroinflammation J. Neurol. Neurosurg. Psychiatry, October 1, 2003; 74(10): 1364 - 1370. [Abstract] [Full Text] [PDF]
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K. Akassoglou, E. Douni, J. Bauer, H. Lassmann, G. Kollias, and L. Probert Exclusive tumor necrosis factor (TNF) signaling by the p75TNF receptor triggers inflammatory ischemia in the CNS of transgenic mice PNAS, January 21, 2003; 100(2): 709 - 714. [Abstract] [Full Text] [PDF]
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L. Yang, K. Lindholm, Y. Konishi, R. Li, and Y. Shen Target Depletion of Distinct Tumor Necrosis Factor Receptor Subtypes Reveals Hippocampal Neuron Death and Survival through Different Signal Transduction Pathways J. Neurosci., April 15, 2002; 22(8): 3025 - 3032. [Abstract] [Full Text] [PDF]
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S.-C. Chen, M. W. Leach, Y. Chen, X.-Y. Cai, L. Sullivan, M. Wiekowski, B. J. Dovey-Hartman, A. Zlotnik, and S. A. Lira Central Nervous System Inflammation and Neurological Disease in Transgenic Mice Expressing the CC Chemokine CCL21 in Oligodendrocytes J. Immunol., February 1, 2002; 168(3): 1009 - 1017. [Abstract] [Full Text] [PDF]
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 J. L. Daigle, J.-H. Hong, C.-S. Chiang, and W. H. McBride The Role of Tumor Necrosis Factor Signaling Pathways in the Response of Murine Brain to Irradiation Cancer Res., December 1, 2001; 61(24): 8859 - 8865. [Abstract] [Full Text] [PDF]
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 B. Kornek, M. K. Storch, J. Bauer, A. Djamshidian, R. Weissert, E. Wallstroem, A. Stefferl, F. Zimprich, T. Olsson, C. Linington, et al. Distribution of a calcium channel subunit in dystrophic axons in multiple sclerosis and experimental autoimmune encephalomyelitis Brain, June 1, 2001; 124(6): 1114 - 1124. [Abstract] [Full Text] [PDF]
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G. Kassiotis and G. Kollias Uncoupling the Proinflammatory from the Immunosuppressive Properties of Tumor Necrosis Factor (Tnf) at the P55 TNF Receptor Level: Implications for Pathogenesis and Therapy of Autoimmune Demyelination J. Exp. Med., February 19, 2001; 193(4): 427 - 434. [Abstract] [Full Text] [PDF]
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A. Weishaupt, S. Jander, W. Bruck, T. Kuhlmann, M. Stienekemeier, T. Hartung, K. V. Toyka, G. Stoll, and R. Gold Molecular Mechanisms of High-Dose Antigen Therapy in Experimental Autoimmune Encephalomyelitis: Rapid Induction of Th1-Type Cytokines and Inducible Nitric Oxide Synthase J. Immunol., December 15, 2000; 165(12): 7157 - 7163. [Abstract] [Full Text] [PDF]
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L. Jin, D. P. Raymond, T. D. Crabtree, S. J. Pelletier, C. W. Houlgrave, T. L. Pruett, and R. G. Sawyer Enhanced Murine Macrophage TNF Receptor Shedding by Cytosine-Guanine Sequences in Oligodeoxynucleotides J. Immunol., November 1, 2000; 165(9): 5153 - 5160. [Abstract] [Full Text] [PDF]
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W.-X. Huang, P. Huang, A. Gomes, and J. Hillert Apoptosis mediators FasL and TRAIL are upregulated in peripheral blood mononuclear cells in MS Neurology, October 10, 2000; 55(7): 928 - 934. [Abstract] [Full Text] [PDF]
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L. Probert, H.-P. Eugster, K. Akassoglou, J. Bauer, K. Frei, H. Lassmann, and A. Fontana TNFR1 signalling is critical for the development of demyelination and the limitation of T-cell responses during immune-mediated CNS disease Brain, October 1, 2000; 123(10): 2005 - 2019. [Abstract] [Full Text] [PDF]
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 J. Xaus, M. Comalada, A. F. Valledor, J. Lloberas, F. Lopez-Soriano, J. M. Argiles, C. Bogdan, and A. Celada LPS induces apoptosis in macrophages mostly through the autocrine production of TNF-alpha Blood, June 15, 2000; 95(12): 3823 - 3831. [Abstract] [Full Text] [PDF]
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 K. Akassoglou, K. W. Kombrinck, J. L. Degen, and S. Strickland Tissue Plasminogen Activator-Mediated Fibrinolysis Protects against Axonal Degeneration and Demyelination after Sciatic Nerve Injury J. Cell Biol., May 29, 2000; 149(5): 1157 - 1166. [Abstract] [Full Text] [PDF]
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W.-K. Kim, Y. Kan, D. Ganea, R. P. Hart, I. Gozes, and G. M. Jonakait Vasoactive Intestinal Peptide and Pituitary Adenylyl Cyclase-Activating Polypeptide Inhibit Tumor Necrosis Factor-alpha Production in Injured Spinal Cord and in Activated Microglia via a cAMP-Dependent Pathway J. Neurosci., May 15, 2000; 20(10): 3622 - 3630. [Abstract] [Full Text] [PDF]
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 C. L. Delaney and E. L. Feldman Review {blacksquare} : Insulin-like Growth Factor-I and Apoptosis in Glial Cell Biology Neuroscientist, February 1, 2000; 6(1): 39 - 47. [Abstract] [PDF]
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L. Soane, H. Rus, F. Niculescu, and M. L. Shin Inhibition of Oligodendrocyte Apoptosis by Sublytic C5b-9 Is Associated with Enhanced Synthesis of Bcl-2 and Mediated by Inhibition of Caspase-3 Activation J. Immunol., December 1, 1999; 163(11): 6132 - 6138. [Abstract] [Full Text] [PDF]
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 P. Ye and A. J. D’Ercole Insulin-Like Growth Factor I Protects Oligodendrocytes from Tumor Necrosis Factor-{alpha}-Induced Injury Endocrinology, July 1, 1999; 140(7): 3063 - 3072. [Abstract] [Full Text]
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 A. Rogove, C Siao, B Keyt, S Strickland, and S. Tsirka Activation of microglia reveals a non-proteolytic cytokine function for tissue plasminogen activator in the central nervous system J. Cell Sci., January 11, 1999; 112(22): 4007 - 4016. [Abstract] [PDF]
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