title: Tumor necrosis factor p55 and p75 receptors are involved in chemical-induced apoptosis of dentate granule neurons.
abstract: Localized tumor necrosis factor-alpha (TNFalpha) elevation has diverse effects in brain injury often attributed to signaling via TNFp55 or TNFp75 receptors. Both dentate granule cells and CA pyramidal cells express TNF receptors (TNFR) at low levels in a punctate pattern. Using a model to induce selective death of dentate granule cells (trimethyltin; 2 mg/kg, i.p.), neuronal apoptosis [terminal deoxynucleotidyl transferase-mediated dUTP-biotin in situ end labeling, active caspase 3 (AC3)] was accompanied by amoeboid microglia and elevated TNFalpha mRNA levels. TNFp55R (55 kDa type-1 TNFR) and TNFp75R (75 kDa type-2 TNFR) immunoreactivity in AC3(+) neurons displayed a pattern suggestive of receptor internalization and a temporal sequence of expression of TNFp55R followed by TNFp75R associated with the progression of apoptosis. A distinct ramified microglia response occurred around CA1 neurons and healthy dentate neurons that displayed an increase in the normal punctate pattern of TNFRs. Neuronal damage was decreased with i.c.v. injection of TNFalpha antibody and in TNFp55R-/-p75R-/- mice that showed higher constitutive mRNA levels for interleukin (IL-1alpha), macrophage inflammatory protein 1-alpha (MIP-1alpha), TNFalpha, transforming growth factor beta1, Fas, and TNFRSF6-assoicated via death domain (FADD). TNFp75R-/- mice showed exacerbated injury and elevated mRNA levels for IL-1alpha, MIP-1alpha, and TNFalpha. In TNFp55R-/- mice, constitutive mRNA levels for TNFalpha, IL-6, caspase 8, FADD, and Fas-associated phosphatase were higher; IL-1alpha, MIP-1alpha, and transforming growth factor beta1 lower. The mice displayed exacerbated neuronal death, delayed microglia response, increased FADD and TNFp75R mRNA levels, and co-expression of TNFp75R in AC3(+) neurons. The data demonstrate TNFR-mediated apoptotic death of dentate granule neurons utilizing both TNFRs and suggest a TNFp75R-mediated apoptosis in the absence of normal TNFp55R activity.
authors: Department of Health and Human Services, Neurotoxicology Group, Laboratory of Neurobiology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA. harry@niehs.nih.gov
authors: G Jean
authors: GJ
authors: Harry
authors: Christian
authors: C
authors: Lefebvre d'Hellencourt
authors: Christopher A
authors: CA
authors: McPherson
authors: Jason A
authors: JA
authors: Funk
authors: Mineyoshi
authors: M
authors: Aoyama
authors: Robert N
authors: RN
authors: Wine
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D018891:Dentate Gyrus / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology; D053200:Fas-Associated Death Domain Protein / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000276:immunology; D009410:Nerve Degeneration / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D009498:Neurotoxins / Q000633:toxicity; D017475:Receptors, Nerve Growth Factor / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D014298:Trimethyltin Compounds / Q000633:toxicity
chemical_list: D051017:Apoptosis Regulatory Proteins; D016207:Cytokines; C505534:Fadd protein, mouse; D053200:Fas-Associated Death Domain Protein; D009498:Neurotoxins; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; C517634:Ngfr protein, mouse; D014298:Trimethyltin Compounds; C046488:trimethyltin