Abstract
Recently, we have demonstrated that tumor necrosis factor-alpha (TNF-alpha) rescues retinal ganglion cells (RGCs) from retrograde cell death in vivo after axotomy of the optic nerve. The mechanism of RGC rescue was dependent on TNF-receptor I-mediated potassium current reduction and consecutive activation of the phosphatidylinositol 3-kinase (PI3-K)/Akt pathway. Here, we present evidence that interleukin-1 beta (IL-1 beta) also promotes RGC survival, but shows distinct differences with respect to its neuroprotective mechanisms. Using whole-cell and outside-out patch-clamp techniques, we observed that IL-1 beta decreased both inward sodium current amplitudes and outward potassium current amplitudes. Counteracting these effects by sodium or potassium channel opening inhibited the survival-promoting effects of this cytokine. IL-1 beta-induced current reduction could not be abolished by the interleukin-1 receptor antagonist, indicating that the electrophysiological effects of IL-1 beta are independent of interleukin-1 receptor I (IL-1RI) activation. Western blot analysis revealed an IL-1 beta-induced IL-1RI-dependent upregulation of phospho-Akt. Antagonism of the survival-promoting effects of IL-1 beta by PI3-K inhibition revealed the functional relevance of the PI3-K/Akt pathway in IL-1 beta-induced signal transduction in vivo.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Axotomy
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Cell Membrane / drug effects
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Cell Membrane / metabolism
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Cell Survival / drug effects
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Cell Survival / physiology*
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Cells, Cultured
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Enzyme Inhibitors / pharmacology
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Female
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Interleukin 1 Receptor Antagonist Protein
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Interleukin-1 / metabolism*
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Interleukin-1 / pharmacology
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Membrane Potentials / drug effects
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Membrane Potentials / physiology
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Nerve Degeneration / metabolism*
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Nerve Degeneration / physiopathology
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Neuroprotective Agents / metabolism*
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Neuroprotective Agents / pharmacology
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Optic Nerve / surgery
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Phosphorylation / drug effects
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Potassium Channels / drug effects
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Potassium Channels / metabolism*
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Protein Serine-Threonine Kinases*
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Proto-Oncogene Proteins / drug effects
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-akt
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Rats
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Rats, Sprague-Dawley
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Receptors, Interleukin-1 / drug effects
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Receptors, Interleukin-1 / metabolism
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Receptors, Interleukin-1 Type I
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Retinal Ganglion Cells / cytology
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Retinal Ganglion Cells / drug effects
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Retinal Ganglion Cells / metabolism*
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Sialoglycoproteins / pharmacology
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Signal Transduction / drug effects
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Signal Transduction / physiology
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Sodium Channels / drug effects
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Sodium Channels / metabolism*
Substances
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Enzyme Inhibitors
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Interleukin 1 Receptor Antagonist Protein
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Interleukin-1
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Neuroprotective Agents
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Phosphoinositide-3 Kinase Inhibitors
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Potassium Channels
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Proto-Oncogene Proteins
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Receptors, Interleukin-1
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Receptors, Interleukin-1 Type I
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Sialoglycoproteins
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Sodium Channels
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Akt1 protein, rat
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt