Alternate Pathways Preserve Tumor Necrosis Factor-α Production After Nuclear Factor-κB Inhibition in Neonatal Cerebral Hypoxia-Ischemia
Alternate Pathways Preserve Tumor Necrosis Factor-α Production After Nuclear Factor-κB Inhibition in Neonatal Cerebral Hypoxia-Ischemia
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DOI：
10.1161/strokeaha.109.560250
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发表时间：
2009-10-01
期刊：
影响因子：
8.3
通讯作者：
Kavelaars, Annemieke
中科院分区：
文献类型：
--
作者：
Nijboer, Cora H.;Heijnen, Cobi J.;Kavelaars, Annemieke
背景与目的：核因子-kappaB(NF-kappa B)是炎症和细胞凋亡的重要调节因子。我们先前的研究表明，通过TAT-NBD治疗抑制核因子-kappaB可显著减轻新生儿缺氧缺血性脑损伤。TAT-NBD的神经保护作用与抑制脑细胞因子的产生无关。我们研究了肿瘤坏死因子-α(TNF-α)在抑制核因子-kappaB后如何维持其产生，以及肿瘤坏死因子-α是否参与了脑损伤。大鼠缺氧缺血后立即给予TAT-NBD、JNK抑制剂TAT-JBD和/或肿瘤坏死因子-α抑制剂依那西普治疗。我们测定了脑损伤、核因子-kappaB和AP-1活性、GADD45β、XIAP、(P-)TAK1、肿瘤坏死因子-α和肿瘤坏死因子受体的表达。结果--我们的数据证实TAT-NBD治疗在不抑制肿瘤坏死因子-α产生的情况下减轻了脑损伤。我们现在发现，TAT-NBD处理增加了HI诱导的AP-1的激活，同时降低了GADD45β，XIAP，并增加了(P)-TAK1的表达。联合抑制NF-kappaB和JNK/AP-1可抑制HI诱导的肿瘤坏死因子-α的产生。然而，这种治疗降低了单独抑制核因子-kappaB的神经保护作用。我们发现，依那西普在给药后可在HI脑中检测到，而且依那西普治疗也降低了核因子-kappaB抑制的神经保护作用。结论：新生儿脑缺血后抑制核因子-kappaB的表达时，JNK/AP-1的活性增强，是促进肿瘤坏死因子-α表达的必要条件。我们的数据表明，切换到JNK/AP-1激活保留了HI诱导的肿瘤坏死因子-α的表达，从而可能通过肿瘤坏死因子-R2依赖机制参与了TAT-NBD的神经保护作用。(笔划。2009年；40：3362-3368。)
Background and Purpose-Nuclear factor-kappa B (NF-kappa B) is an important regulator of inflammation and apoptosis. We showed previously that NF-kappa B inhibition by intraperitoneal TAT-NBD treatment strongly reduced neonatal hypoxic-ischemic (HI) brain damage. Neuroprotection by TAT-NBD was not associated with inhibition of cerebral cytokine production. We investigated how tumor necrosis factor-alpha (TNF-alpha) production is maintained after NF-kappa B inhibition and whether TNF-alpha contributes to brain damage.Methods-Postnatal Day 7 rats were subjected to unilateral carotid artery occlusion and hypoxia. Rats were treated immediately after HI with TAT-NBD, the JNK inhibitor TAT-JBD, and/or the TNF-alpha inhibitor etanercept. We determined brain damage, NF-kappa B and AP-1 activity, Gadd45 beta, XIAP, (P-) TAK1, TNF-alpha, and TNF receptor expression.Results-Our data confirm that TAT-NBD treatment reduces brain damage without inhibiting TNF-alpha production. We now show that TAT-NBD treatment increased HI-induced AP-1 activation concomitantly with reduced Gadd45 beta, XIAP, and increased (P)-TAK1 expression. Combined inhibition of NF-kappa B and JNK/AP-1 abrogated HI-induced TNF-alpha production. However, this treatment reduced the neuroprotective effect of NF-kappa B inhibition alone. We show that etanercept was detectable in the HI brain after intraperitoneal administration and that etanercept treatment also reduced the neuroprotective effect of NF-kappa B inhibition. Finally, NF-kappa B inhibition decreased HI-induced upregulation of TNF-R1 and increased TNF-R2 expression.Conclusions-When NF-kappa B was inhibited after neonatal cerebral HI, JNK/AP-1 activity was increased and required for increased TNF-alpha expression. Our data indicate that the switch to JNK/AP-1 activation preserves HI-induced TNF-alpha expression and thereby might contribute to the neuroprotective effect of TAT-NBD possibly through a TNF-R2 dependent mechanism. (Stroke. 2009;40:3362-3368.)