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      Erythropoietin-mediated neuroprotection involves cross-talk between Jak2 and NF-kappaB signalling cascades.

      Nature

      metabolism, Tumor Necrosis Factor-alpha, Superoxide Dismutase, Signal Transduction, Receptors, Erythropoietin, Rats, Proto-Oncogene Proteins, Protein-Tyrosine Kinases, Protein Transport, Protein Binding, Nitric Oxide, Neuroprotective Agents, Neurons, NF-kappa B, N-Methylaspartate, Janus Kinase 2, Genes, Reporter, physiology, Erythropoietin, DNA, Cells, Cultured, Cell Nucleus, Apoptosis, Animals

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          Abstract

          Erythropoietin, a kidney cytokine regulating haematopoiesis (the production of blood cells), is also produced in the brain after oxidative or nitrosative stress. The transcription factor hypoxia-inducible factor-1 (HIF-1) upregulates EPO following hypoxic stimuli. Here we show that preconditioning with EPO protects neurons in models of ischaemic and degenerative damage due to excitotoxins and consequent generation of free radicals, including nitric oxide (NO). Activation of neuronal EPO receptors (EPORs) prevents apoptosis induced by NMDA (N-methyl-d-aspartate) or NO by triggering cross-talk between the signalling pathways of Janus kinase-2 (Jak2) and nuclear factor-kappaB (NF-kappaB). We show that EPOR-mediated activation of Jak2 leads to phosphorylation of the inhibitor of NF-kappaB (IkappaB), subsequent nuclear translocation of the transcription factor NF-kappaB, and NF-kappaB-dependent transcription of neuroprotective genes. Transfection of cerebrocortical neurons with a dominant interfering form of Jak2 or an IkappaBalpha super-repressor blocks EPO-mediated prevention of neuronal apoptosis. Thus neuronal EPORs activate a neuroprotective pathway that is distinct from previously well characterized Jak and NF-kappaB functions. Moreover, this EPO effect may underlie neuroprotection mediated by hypoxic-ischaemic preconditioning.

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          Most cited references 20

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          An essential role for NF-kappaB in preventing TNF-alpha-induced cell death.

          Studies on mice deficient in nuclear factor kappa B (NF-kappaB) subunits have shown that this transcription factor is important for lymphocyte responses to antigens and cytokine-inducible gene expression. In particular, the RelA (p65) subunit is required for induction of tumor necrosis factor-alpha (TNF-alpha)-dependent genes. Treatment of RelA-deficient (RelA-/-) mouse fibroblasts and macrophages with TNF-alpha resulted in a significant reduction in viability, whereas RelA+/+ cells were unaffected. Cytotoxicity to both cell types was mediated by TNF receptor 1. Reintroduction of RelA into RelA-/- fibroblasts resulted in enhanced survival, demonstrating that the presence of RelA is required for protection from TNF-alpha. These results have implications for the treatment of inflammatory and proliferative diseases.
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            Suppression of TNF-alpha -Induced Apoptosis by NF-kappa B

             S Martin,  D Green,  I Verma (1996)
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              Apoptosis and necrosis: two distinct events induced, respectively, by mild and intense insults with N-methyl-D-aspartate or nitric oxide/superoxide in cortical cell cultures.

              N-Methyl-D-aspartate (NMDA) receptor-mediated neurotoxicity may depend, in part, on the generation of nitric oxide (NO.) and superoxide anion (O2.-), which react to form peroxynitrite (OONO-). This form of neurotoxicity is thought to contribute to a final common pathway of injury in a wide variety of acute and chronic neurologic disorders, including focal ischemia, trauma, epilepsy, Huntington disease, Alzheimer disease, amyotrophic lateral scelerosis, AIDS dementia, and other neurodegenerative diseases. Here, we report that exposure of cortical neurons to relatively short durations or low concentrations of NMDA, S-nitrosocysteine, or 3-morpholinosydnonimine, which generate low levels of peroxynitrite, induces a delayed form of neurotoxicity predominated by apoptotic features. Pretreatment with superoxide dismutase and catalase to scavenge O2.- partially prevents the apoptotic process triggered by S-nitrosocysteine or 3-morpholinosydnonimine. In contrast, intense exposure to high concentrations of NMDA or peroxynitrite induces necrotic cell damage characterized by acute swelling and lysis, which cannot be ameliorated by superoxide dismutase and catalase. Thus, depending on the intensity of the initial insult, NMDA or nitric oxide/superoxide can result in either apoptotic or necrotic neuronal cell damage.
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                Author and article information

                Journal
                10.1038/35088074
                11493922

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