title: Tumor necrosis factor receptor deletion reduces nuclear factor-kappaB activation, cellular inhibitor of apoptosis protein 2 expression, and functional recovery after traumatic spinal cord injury.
abstract: Tumor necrosis factor-alpha (TNF-alpha) expression has been documented extensively in animal models of traumatic spinal cord injury (SCI). However, the pathophysiological significance of TNF-alpha expression in the injured cord remains to be delineated. The TNF receptor (TNFR)-nuclear factor-kappaB (NF-kappaB) signal transduction pathway is important for maintaining cell viability. NF-kappaB exerts anti-apoptotic effects via an endogenous caspase inhibitory system mediated by cellular inhibitor of apoptosis protein 2 (c-IAP2). NF-kappaB 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-kappaB in relation to SCI pathology and functional recovery. Nuclear proteins from the injured cords of the TNFR1(-/-) mice had a reduced NF-kappaB binding activity compared with the wild-type controls. This decrease in NF-kappaB 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-kappaB pathway is beneficial for limiting apoptotic cell death after SCI and that a defective TNFR-NF-kappaB 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-kappaB, and c-IAP2 may be of pathophysiological importance.
authors.affiliation: Departments of Neurology and Center for the Study of Nervous System Injury, and Radiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: G M
authors.initials: GM
authors.lastname: Kim
authors.forename: J
authors.initials: J
authors.lastname: Xu
authors.forename: J
authors.initials: J
authors.lastname: Xu
authors.forename: S K
authors.initials: SK
authors.lastname: Song
authors.forename: P
authors.initials: P
authors.lastname: Yan
authors.forename: G
authors.initials: G
authors.lastname: Ku
authors.forename: X M
authors.initials: XM
authors.lastname: Xu
authors.forename: C Y
authors.initials: CY
authors.lastname: Hsu
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D017209:Apoptosis; D001369:Axons / Q000473:pathology; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D005260:Female; D020287:In Situ Nick-End Labeling; D051034:Inhibitor of Apoptosis Proteins; D008279:Magnetic Resonance Imaging; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009043:Motor Activity; D009186:Myelin Sheath / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency* / Q000235:genetics; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D020127:Recovery of Function; D015398:Signal Transduction / Q000502:physiology; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D013119:Spinal Cord Injuries / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D044767:Ubiquitin-Protein Ligases; D014949:Wounds, Nonpenetrating
chemical_list: D015703:Antigens, CD; D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; D011506:Proteins; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; C494835:Birc3 protein, mouse; D044767:Ubiquitin-Protein Ligases; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases