Erythropoietin-mediated neuroprotection involves cross-talk between Jak2 and NF-kappaB signalling cascades.
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.
Digicaylioglu
M
M
Center for Neuroscience and Aging Research, The Burnham Institute, La Jolla, CA 92037, USA.
Lipton
S A
SA
D000818:Animals; D017209:Apoptosis; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D004921:Erythropoietin / Q000378:metabolism / Q000502:physiology*; D017930:Genes, Reporter; D053614:Janus Kinase 2; D016202:N-Methylaspartate; D016328:NF-kappa B / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D051381:Rats; D017467:Receptors, Erythropoietin / Q000378:metabolism; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016328:NF-kappa B; D018696:Neuroprotective Agents; D011518:Proto-Oncogene Proteins; D017467:Receptors, Erythropoietin; D014409:Tumor Necrosis Factor-alpha; D004921:Erythropoietin; D009569:Nitric Oxide; D016202:N-Methylaspartate; D004247:DNA; D013482:Superoxide Dismutase; D011505:Protein-Tyrosine Kinases; C507927:Jak2 protein, rat; D053614:Janus Kinase 2