Erythropoietin-mediated neuroprotection involves cross-talk between Jak2 and NF-κB signalling cascades
- 9 August 2001
- journal article
- letter
- Published by Springer Science and Business Media LLC in Nature
- Vol. 412 (6847), 641-647
- https://doi.org/10.1038/35088074
Abstract
Erythropoietin, a kidney cytokine regulating haematopoiesis (the production of blood cells), is also produced in the brain after oxidative or nitrosative stress1,2. The transcription factor hypoxia-inducible factor-1 (HIF-1) upregulates EPO following hypoxic stimuli3,4. Here we show that preconditioning with EPO protects neurons in models of ischaemic and degenerative damage due to excitotoxins4,5 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-κB (NF-κB). We show that EPOR-mediated activation of Jak2 leads to phosphorylation of the inhibitor of NF-κB (IκB), subsequent nuclear translocation of the transcription factor NF-κB, and NF-κB-dependent transcription of neuroprotective genes. Transfection of cerebrocortical neurons with a dominant interfering form of Jak2 or an IκBα 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-κB functions. Moreover, this EPO effect may underlie neuroprotection mediated by hypoxic–ischaemic preconditioning.Keywords
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