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The Journal of Neuroscience, September 1, 2001, 21(17):6617-6625
Tumor Necrosis Factor Receptor Deletion Reduces Nuclear
Factor- B Activation, Cellular Inhibitor of Apoptosis Protein 2 Expression, and Functional Recovery after Traumatic Spinal Cord
Injury
Gyeong-Moon
Kim1,
Jan
Xu1,
Jinming
Xu1,
Sheng-Kwei
Song2,
Ping
Yan3,
Grace
Ku1,
Xiao Ming
Xu3, and
Chung Y.
Hsu1
Departments of 1 Neurology and Center for the Study of
Nervous System Injury, and 2 Radiology, Washington
University School of Medicine, St. Louis, Missouri 63110, and
3 Department of Anatomy and Neurobiology, St. Louis
University School of Medicine, St. Louis, Missouri 63104
Tumor necrosis factor- (TNF-) expression has been documented
extensively in animal models of traumatic spinal cord injury (SCI).
However, the pathophysiological significance of TNF- expression in
the injured cord remains to be delineated. The TNF receptor (TNFR)-nuclear factor- B (NF-B) signal transduction pathway is important for maintaining cell viability. NF-B exerts anti-apoptotic effects via an endogenous caspase inhibitory system mediated by cellular inhibitor of apoptosis protein 2 (c-IAP2). NF-B
transactivates c-IAP2 to inhibit caspase-3 activation. Progressive cell
death, including morphological and biochemical features suggestive of apoptosis, has been noted after SCI. We explored the effects of TNFR1
or TNFR2 deletion on the apoptotic events downstream of NF-B in
relation to SCI pathology and functional recovery. Nuclear proteins
from the injured cords of the TNFR1 / mice had a
reduced NF-B binding activity compared with the wild-type controls.
This decrease in NF-B activation was accompanied by a reduction in
c-IAP2 expression and an increase in the active form of caspase-3
protein. After SCI the TNFR1/ mice had greater
numbers of apoptotic cells, a larger lesion size, and worse functional
recovery than wild-type mice. TNFR2-deficient mice had a similar,
although not as pronounced, consequence as the
TNFR1/ mice. These findings support the argument
that the TNFR-NF-B pathway is beneficial for limiting apoptotic
cell death after SCI and that a defective TNFR-NF-B pathway results
in a poorer neurological outcome. A worse functional outcome in
TNFR/ mice suggests that an endogenous apoptosis
inhibitory mechanism mediated by TNFR activation, NF-B, and c-IAP2
may be of pathophysiological importance.
Key words:
apoptosis; caspase-3; tumor necrosis factor; TNFR1; TNFR2; cytokine
Copyright © 2001 Society for Neuroscience 0270-6474/01/21176617-09$05.00/0
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