Alternate pathways preserve tumor necrosis factor-α production after nuclear factor-κB inhibition in neonatal cerebral hypoxia-ischemia

Abstract

Background and Purpose-: Nuclear factor-κB (NF-κB) is an important regulator of inflammation and apoptosis. We showed previously that NF-κB 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-α (TNF-α) production is maintained after NF-κB inhibition and whether TNF-α 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-α inhibitor etanercept. We determined brain damage, NF-κB and AP-1 activity, Gadd45β, XIAP, (P-)TAK1, TNF-α, and TNF receptor expression. Results-: Our data confirm that TAT-NBD treatment reduces brain damage without inhibiting TNF-α production. We now show that TAT-NBD treatment increased HI-induced AP-1 activation concomitantly with reduced Gadd45β, XIAP, and increased (P)-TAK1 expression. Combined inhibition of NF-κB and JNK/AP-1 abrogated HI-induced TNF-α production. However, this treatment reduced the neuroprotective effect of NF-κB 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-κB inhibition. Finally, NF-κB inhibition decreased HI-induced upregulation of TNF-R1 and increased TNF-R2 expression. Conclusions-: When NF-κB was inhibited after neonatal cerebral HI, JNK/AP-1 activity was increased and required for increased TNF-α expression. Our data indicate that the switch to JNK/AP-1 activation preserves HI-induced TNF-α expression and thereby might contribute to the neuroprotective effect of TAT-NBD possibly through a TNF-R2 dependent mechanism. © 2009 American Heart Association, Inc.