Abstract
Tumor necrosis factor (TNF) is an important factor in various acute and chronic neurodegenerative disorders. In retinal ischemia, we show early, transient upregulation of TNF, TNF receptor 1 (TNF-R1), and TNF-R2 6 hr after reperfusion preceding neuronal cell loss. To assess the specific role of TNF and its receptors, we compared ischemia-reperfusion-induced retinal damage in mice deficient for TNF-R1, TNF-R2, or TNF by quantifying neuronal cell loss 8 d after the insult. Surprisingly, TNF deficiency did not affect overall cell loss, yet absence of TNF-R1 led to a strong reduction of neurodegeneration and lack of TNF-R2 led to an enhancement of neurodegeneration, indicative of TNF-independent and TNF-dependent processes in the retina, with TNF-R1 augmenting neuronal death and TNF-R2 promoting neuroprotection. Western blot analyses of retinas revealed that reduction of neuronal cell loss in TNF-R1/ animals correlated with the presence of activated Akt/protein kinase B (PKB). Inhibition of the phosphatidylinositol 3-kinase signaling pathway reverted neuroprotection in TNF-R1-deficient mice, indicating an instrumental role of Akt/PKB in neuroprotection and TNF-R2 dependence of this pathway. Selective inhibition of TNF-R1 function may represent a new approach to reduce ischemia-induced neuronal damage, being potentially superior to strategies aimed at suppression of TNF activity in general.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, CD / genetics
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Antigens, CD / metabolism*
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Blotting, Western
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Cell Count
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Cell Death / drug effects
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Cytoprotection / drug effects
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Cytoprotection / genetics
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Disease Models, Animal
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Mice
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Mice, Knockout
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Neurons / drug effects
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Neurons / pathology
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Protein Serine-Threonine Kinases*
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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Receptors, Tumor Necrosis Factor / deficiency
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Receptors, Tumor Necrosis Factor / genetics
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Receptors, Tumor Necrosis Factor / metabolism*
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Receptors, Tumor Necrosis Factor, Type I
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Receptors, Tumor Necrosis Factor, Type II
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Reperfusion Injury / pathology
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Reperfusion Injury / physiopathology*
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Retina / enzymology
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Retina / pathology
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Retina / physiopathology*
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Retinal Diseases / drug therapy
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Retinal Diseases / pathology
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Retinal Diseases / physiopathology*
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Retinal Vessels / pathology
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Retinal Vessels / physiopathology
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Signal Transduction / drug effects
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Tumor Necrosis Factor-alpha / deficiency
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / metabolism
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Tumor Necrosis Factor-alpha / pharmacology*
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Up-Regulation
Substances
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Antigens, CD
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Phosphoinositide-3 Kinase Inhibitors
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Proto-Oncogene Proteins
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Receptors, Tumor Necrosis Factor
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Receptors, Tumor Necrosis Factor, Type I
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Receptors, Tumor Necrosis Factor, Type II
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Tumor Necrosis Factor-alpha
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt