title: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) signaling and cell death in the immature central nervous system after hypoxia-ischemia and inflammation.
abstract: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family. The interaction of TRAIL with death receptor 4 (DR4) and DR5 can trigger apoptotic cell death. The aim of this study was to investigate the role of TRAIL signaling in neonatal hypoxia-ischemia (HI). Using a neonatal mouse model of HI, mRNA, and protein expression of TRAIL, DR5 and the TRAIL decoy receptors osteoprotegerin (OPG), mDcTRAILR1, and mDcTRAILR2 were determined. In vitro, mRNA expression of these genes was measured in primary neurons and oligodendrocyte progenitor cells (OPCs) after inflammatory cytokine (TNF-α/IFN-γ) treatment and/or oxygen and glucose deprivation (OGD). The toxicity of these various paradigms was also measured. The expression of TRAIL, DR5, OPG, and mDcTRAILR2 was significantly increased after HI. In vitro, inflammatory cytokines and OGD treatment significantly induced mRNAs for TRAIL, DR5, OPG, and mDcTRAILR2 in primary neurons and of TRAIL and OPG in OPCs. TRAIL protein was expressed primarily in microglia and astroglia, whereas DR5 co-localized with neurons and OPCs in vivo. OGD enhanced TNF-α/IFN-γ toxicity in both neuronal and OPC cultures. Recombinant TRAIL exerted toxicity alone or in combination with OGD and TNF-α/IFN-γ in primary neurons but not in OPC cultures. The marked increases in the expression of TRAIL and its receptors after cytokine exposure and OGD in primary neurons and OPCs were similar to those found in our animal model of neonatal HI. The toxicity of TRAIL in primary neurons suggests that TRAIL signaling participates in neonatal brain injury after inflammation and HI.
authors: From the Centre for the Developing Brain, Perinatal Brain Injury Group, Kings College London, London SE1 7EH, United Kingdom.
authors: Anton
authors: A
authors: Kichev
authors: Catherine I
authors: CI
authors: Rousset
authors: Ana A
authors: AA
authors: Baburamani
authors: Steven W
authors: SW
authors: Levison
authors: Teresa L
authors: TL
authors: Wood
authors: Pierre
authors: P
authors: Gressens
authors: Claire
authors: C
authors: Thornton
authors: Henrik
authors: H
authors: Hagberg
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002490:Central Nervous System / Q000473:pathology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000172:deficiency; D000860:Hypoxia / Q000378:metabolism / Q000473:pathology*; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D007371:Interferon-gamma / Q000494:pharmacology; D007511:Ischemia / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009836:Oligodendroglia / Q000473:pathology; D010100:Oxygen / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013234:Stem Cells / Q000187:drug effects / Q000473:pathology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D005947:Glucose; D010100:Oxygen
keywords: Cell Death; Hypoxia; Immature CNS; Neuroinflammation; Neurons; Oligodendrocytes; Trail