Interleukin-1 beta protects neurons via the interleukin-1 (IL-1) receptor-mediated Akt pathway and by IL-1 receptor-independent decrease of transmembrane currents in vivo.
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.
Neurologische Universitätsklinik, Robert-Koch-Strasse 40, D-37075 Göttingen, Germany. rdiem@gwdg.de
Ricarda
R
Diem
Muriel
M
Hobom
Philipp
P
Grötsch
Birgit
B
Kramer
Mathias
M
Bähr
D000818:Animals; D019771:Axotomy; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000378:metabolism* / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009410:Nerve Degeneration / Q000378:metabolism* / Q000503:physiopathology; D018696:Neuroprotective Agents / Q000378:metabolism* / Q000494:pharmacology; D009900:Optic Nerve / Q000601:surgery; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017207:Rats, Sprague-Dawley; D017472:Receptors, Interleukin-1 / Q000187:drug effects / Q000378:metabolism; D053573:Receptors, Interleukin-1 Type I; D012165:Retinal Ganglion Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D012795:Sialoglycoproteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism*
D004791:Enzyme Inhibitors; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D018696:Neuroprotective Agents; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015221:Potassium Channels; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D017472:Receptors, Interleukin-1; D053573:Receptors, Interleukin-1 Type I; D012795:Sialoglycoproteins; D015222:Sodium Channels; C494920:Akt1 protein, rat