Tumor necrosis factor-like weak inducer of apoptosis-induced neurodegeneration.
Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the tumor necrosis factor (TNF) family of cytokines. It has proangiogenic and proinflammatory properties in vivo and induces cell death in tumor cell lines. TWEAK effects are mediated by the membrane receptor Fn14. In a systematic search for genes regulated in a murine stroke model with the tag-sequencing technique massively parallel signature sequencing, we have identified TWEAK as an induced gene. After 24 hr of focal cerebral ischemia in vivo or oxygen glucose deprivation in primary cortical neurons, both TWEAK and its receptor Fn14 were significantly upregulated. TWEAK induced cell death in primary neurons. Transfection of a nuclear factor (NF)-kappaB-luciferase fusion gene demonstrated that TWEAK stimulated transcriptional activity of NF-kappaB through Fn14 and the IkappaB kinase. Inhibition of NF-kappaB reduced TWEAK-stimulated neuronal cell death, suggesting that NF-kappaB mediates TWEAK-induced neurodegeneration at least in part. Intraperitoneal injection of a neutralizing anti-TWEAK antibody significantly reduced the infarct size after 48 hr of permanent cerebral ischemia. In summary, our data show that TWEAK induces neuronal cell death and is involved in neurodegeneration in vivo.
Potrovita
Ioana
I
Department of Neurology, University of Heidelberg, D-69120 Heidelberg, Germany.
Zhang
Wen
W
Burkly
Linda
L
Hahm
Kyungmin
K
Lincecum
John
J
Wang
Monica Z
MZ
Maurer
Martin H
MH
Rossner
Moritz
M
Schneider
Armin
A
Schwaninger
Markus
M
D000818:Animals; D000906:Antibodies / Q000008:administration & dosage / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins; D002545:Brain Ischemia / Q000150:complications / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D016923:Cell Death / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D002544:Cerebral Infarction / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D000074049:Cytokine TWEAK; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D006801:Humans; D051550:I-kappa B Kinase; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D016328:NF-kappa B / Q000096:biosynthesis / Q000235:genetics; D009410:Nerve Degeneration / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D020521:Stroke / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D000074050:TWEAK Receptor; D014162:Transfection; D048069:Tumor Necrosis Factors; D015854:Up-Regulation / Q000235:genetics
D000906:Antibodies; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D000074049:Cytokine TWEAK; D016328:NF-kappa B; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; C000613297:TNFRSF12A protein, human; C109743:TNFSF12 protein, human; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; D048069:Tumor Necrosis Factors; D012313:RNA; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse