Tumor necrosis factor alpha increases neuronal vulnerability to excitotoxic necrosis by inducing expression of the AMPA-glutamate receptor subunit GluR1 via an acid sphingomyelinase- and NF-kappaB-dependent mechanism.
Acid sphingomyelinase (ASMase) and NF-kappaB participate in tumor necrosis factor alpha (TNFalpha) signal transduction. Mice in which the genes encoding ASMase or the p50 subunit of NF-kappaB are disrupted have been reported to be less vulnerable than wild-type mice to focal brain ischemia. We now demonstrate selective diminution in expression of GluR1, an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate-type glutamate receptor (AMPA-GluR) protein subunit, in these two groups of knockout mice. To confirm that neuronal GluR1 expression is regulated by ASMase and NF-kappaB, and to learn whether this regulation has pathophysiological significance, we treated cultured human NT2-N neurons with TNFalpha. This induced GluR1 expression and increased susceptibility of the neurons to kainate necrosis. Both induction of GluR1 and heightened vulnerability to kainate were blocked by inhibiting ASMase or by antisense knockdown of NF-kappaB p50. We conclude that TNFalpha can sensitize neurons to excitotoxic necrosis by inducing expression of GluR1 via an ASMase- and NF-kappaB-dependent mechanism. TNFalpha levels are frequently elevated during ischemia and other CNS diseases in which excitotoxicity contributes to neuronal loss. Our results suggest that inhibiting TNFalpha signal transduction will diminish neuronal necrosis in these diseases.
Yu
ZaiFang
Z
Department of Neurology Research, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
Cheng
Guanjun
G
Wen
Xiaoming
X
Wu
Gary D
GD
Lee
Wang-Tso
WT
Pleasure
David
D
D000818:Animals; D000906:Antibodies; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000737:chemistry; D015870:Gene Expression / Q000187:drug effects; D006624:Hippocampus / Q000737:chemistry; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit; D009336:Necrosis; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009498:Neurotoxins / Q000494:pharmacology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D018091:Receptors, AMPA / Q000032:analysis / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects; D013108:Sphingomyelin Phosphodiesterase / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000906:Antibodies; D000970:Antineoplastic Agents; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D009498:Neurotoxins; D016376:Oligonucleotides, Antisense; D018091:Receptors, AMPA; D013108:Sphingomyelin Phosphodiesterase; D014409:Tumor Necrosis Factor-alpha