Alternate pathways preserve tumor necrosis factor-alpha production after nuclear factor-kappaB inhibition in neonatal cerebral hypoxia-ischemia.
OBJECTIVE
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.
Nijboer
Cora H
CH
Laboratory of Psychoneuroimmunology, University Medical Center Utrecht, Utrecht, The Netherlands.
Heijnen
Cobi J
CJ
Groenendaal
Floris
F
van Bel
Frank
F
Kavelaars
Annemieke
A
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D018797:Cell Cycle Proteins / Q000187:drug effects / Q000378:metabolism; D002544:Cerebral Infarction / Q000378:metabolism* / Q000503:physiopathology; D054022:Cerebrum / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000068800:Etanercept; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism* / Q000503:physiopathology; D007074:Immunoglobulin G / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009410:Nerve Degeneration / Q000378:metabolism* / Q000503:physiopathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D009687:Nuclear Proteins / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018124:Receptors, Tumor Necrosis Factor / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000187:drug effects / Q000378:metabolism; D000097642:GADD45 Proteins
D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D000068800:Etanercept; D007074:Immunoglobulin G; D048031:JNK Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D018696:Neuroprotective Agents; D009687:Nuclear Proteins; D018124:Receptors, Tumor Necrosis Factor; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D051636:X-Linked Inhibitor of Apoptosis Protein; C499073:Gadd45a protein, rat; D000097642:GADD45 Proteins