Alternate Pathways Preserve Tumor Necrosis Factor-alpha Production After Nuclear Factor-kappa B Inhibition in Neonatal Cerebral Hypoxia-Ischemia

作者：Nijboer Cora H; Heijnen Cobi J^*; Groenendaal Floris; van Bel Frank; Kavelaars Annemieke

来源：Stroke, 2009, 40(10): 3362-3368.

DOI：10.1161/STROKEAHA.109.560250

• JNK
• neonatal ischemia
• neuroprotection
• NF-kappa B
• TNF-alpha

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.)

• 出版日期2009-10