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

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-induceble factor-1 (HIF-1) upregulates EPO following hypoxic stimuli. Here we show that preconditioning with EPO protects neurons in models of ischaemic and degeneratve 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-aparte) or NO by triggering cross-talk between the signalling pathways of Janus kinase-2 (Jak2) and nuclear factor-kB (NF-ΚB). We show that EPOR-mediated activation of Jak2 leads to phorylation of the inhibitor of NF-ΚB (IΚB), subsequent nuclear translocation of the transcript factor NF-ΚB, and NF-ΚB dependent transcription of neuroprotective genes. Transfection of cerebrocortical neurons with a dominant interfering form of Jak2 or an IkB∝ super-repressor blocks EPO-mediated prevention of nueronal apoptosis. Thus neuronal EPORs activate a neuroprotective pathway that is distinct from previously well characterizaed Jak and NF-ΚB functions. Moreover, this EPO effect may underlie neuroprotection mediated by hypoxic-ischaemic preconditioning.