Stroke · 2009
Alternate pathways preserve tumor necrosis factor-alpha production after nuclear factor-kappaB inhibition in neonatal cerebral hypoxia-ischemia.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Nijboer Cora H, Heijnen Cobi J, Groenendaal Floris, van Bel Frank, Kavelaars Annemieke
Аннотация
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.
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.
Предметные рубрики MeSH
AnimalsAnimals, NewbornApoptosisCell Cycle ProteinsCerebral InfarctionCerebrumDisease Models, AnimalEnzyme InhibitorsEtanerceptHypoxia-Ischemia, BrainImmunoglobulin GJNK Mitogen-Activated Protein KinasesNF-kappa BNerve DegenerationNeuroprotective AgentsNuclear ProteinsRatsRats, WistarReceptors, Tumor Necrosis FactorSignal TransductionTranscription Factor AP-1Tumor Necrosis Factor-alphaUp-RegulationX-Linked Inhibitor of Apoptosis ProteinGADD45 Proteins