BACKGROUND AND PURPOSE: Nuclear factor-kappaB (NF-kappaB) is an important regulator of inflammation and apoptosis. We showed previously that NF-kappaB 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-kappaB 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-kappaB and AP-1 activity, Gadd45beta, 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 Gadd45beta, XIAP, and increased (P)-TAK1 expression. Combined inhibition of NF-kappaB and JNK/AP-1 abrogated HI-induced TNF-alpha production. However, this treatment reduced the neuroprotective effect of NF-kappaB 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-kappaB inhibition. Finally, NF-kappaB inhibition decreased HI-induced upregulation of TNF-R1 and increased TNF-R2 expression. CONCLUSIONS: When NF-kappaB 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.
BACKGROUND AND PURPOSE: Nuclear factor-kappaB (NF-kappaB) is an important regulator of inflammation and apoptosis. We showed previously that NF-kappaB 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-kappaB 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-kappaB and AP-1 activity, Gadd45beta, 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 Gadd45beta, XIAP, and increased (P)-TAK1 expression. Combined inhibition of NF-kappaB and JNK/AP-1 abrogated HI-induced TNF-alpha production. However, this treatment reduced the neuroprotective effect of NF-kappaB 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-kappaB inhibition. Finally, NF-kappaB inhibition decreased HI-induced upregulation of TNF-R1 and increased TNF-R2 expression. CONCLUSIONS: When NF-kappaB 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.
Authors: Anlys Olivera; Terry W Moore; Fang Hu; Andrew P Brown; Aiming Sun; Dennis C Liotta; James P Snyder; Younghyoun Yoon; Hyunsuk Shim; Adam I Marcus; Andrew H Miller; Thaddeus W W Pace Journal: Int Immunopharmacol Date: 2011-12-22 Impact factor: 4.932
Authors: Cora H Nijboer; Cobi J Heijnen; Hanneke L D M Willemen; Floris Groenendaal; Gerald W Dorn; Frank van Bel; Annemieke Kavelaars Journal: Brain Behav Immun Date: 2009-11-22 Impact factor: 7.217
Authors: Henrik Hagberg; Carina Mallard; Donna M Ferriero; Susan J Vannucci; Steven W Levison; Zinaida S Vexler; Pierre Gressens Journal: Nat Rev Neurol Date: 2015-02-17 Impact factor: 42.937