Tumor necrosis factor receptor deletion reduces nuclear factor-κB activation, cellular inhibitor of apoptosis protein 2 expression, and functional recovery after traumatic spinal cord injury
Tumor necrosis factor receptor deletion reduces nuclear factor-κB activation, cellular inhibitor of apoptosis protein 2 expression, and functional recovery after traumatic spinal cord injury
复制标题
DOI：
10.1523/jneurosci.21-17-06617.2001
复制
发表时间：
2001-09-01
影响因子：
5.3
通讯作者：
Hsu, CY
中科院分区：
文献类型：
--
作者：
Kim, GM;Xu, J;Hsu, CY
肿瘤坏死因子-α（TNF-α）的表达已被广泛记录在创伤性脊髓损伤（SCI）的动物模型。然而，TNF-α在损伤脊髓中表达的病理生理学意义仍有待阐明。肿瘤坏死因子受体（TNFR）-核因子-κ B（NF-kappaB）信号转导通路对于维持细胞活力是重要的。NF-κ B通过细胞凋亡抑制蛋白2（c-IAP 2）介导的内源性半胱天冬酶抑制系统发挥抗凋亡作用。NF-κ B反式激活c-IAP 2以抑制caspase-3激活。SCI后出现进行性细胞死亡，包括提示细胞凋亡的形态学和生化特征。我们探讨了TNFR 1或TNFR 2缺失对NF-κ B下游凋亡事件的影响，这些凋亡事件与SCI病理和功能恢复有关。与野生型对照组相比，TNFR 1（-/-）小鼠受损脊髓的核蛋白具有降低的NF-κ B结合活性。这种NF-κ B活化的减少伴随着c-IAP 2表达的减少和caspase-3蛋白活性形式的增加。SCI后，TNFR 1（-/-）小鼠比野生型小鼠有更多的凋亡细胞，更大的病变大小和更差的功能恢复。TNFR 2缺陷小鼠与TNFR 1（-/-）小鼠具有相似的结果，尽管没有那么明显。这些发现支持了TNFR-NF-kappaB通路有利于限制SCI后凋亡性细胞死亡的论点，并且TNFR-NF-kappaB通路缺陷导致神经学结果较差。TNFR-/-小鼠中更差的功能结果表明，由TNFR激活、NF-κ B和c-IAP 2介导的内源性凋亡抑制机制可能具有病理生理学重要性。
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.