Tumor necrosis factor receptor deletion reduces nuclear factor-kappa B activation, cellular inhibitor of apoptosis protein 2 expression, and functional recovery after traumatic spinal cord injury

Tumor necrosis factor-alpha (TNF-alpha) expression has been documented exte nsively in animal models of traumatic spinal cord injury (SCI). However, th e pathophysiological significance of TNF-alpha expression in the injured co rd remains to be delineated. The TNF receptor (TNFR)-nuclear factor-kappaB (NF-kappaB) signal transduction pathway is important for maintaining cell v iability. 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. Pr ogressive cell death, including morphological and biochemical features sugg estive of apoptosis, has been noted after SCI. We explored the effects of T NFR1 or TNFR2 deletion on the apoptotic events downstream of NF-kappaB in r elation to SCI pathology and functional recovery. Nuclear proteins from the injured cords of the TNFR1(-/-) mice had a reduced NF-kappaB binding activ ity compared with the wild-type controls. This decrease in NF-kappaB activa tion 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 gr eater numbers of apoptotic cells, a larger lesion size, and worse functiona l recovery than wild-type mice. TNFR2-deficient mice had a similar, althoug h not as pronounced, consequence as the TNFR1(-/-) mice. These findings sup port the argument that the TNFR-NF-kappaB pathway is beneficial for limitin g apoptotic cell death after SCI and that a defective TNFR-NF-kappaB pathwa y results in a poorer neurological outcome. A worse functional outcome in T NFR-/- mice suggests that an endogenous apoptosis inhibitory mechanism medi ated by TNFR activation, NF-kappaB, and c-IAP2 may be of pathophysiological importance.