The cytokine erythropoietin is best known for its use in the treatment of anaemia, but work over recent years has shown that it can also protect neurons from apoptosis induced by reactive oxygen and nitrogen species. The mechanism of this protection has remained elusive, but, reporting in Nature, Digicaylioglu and Lipton now provide compelling evidence that preconditioning neurons with erythropoietin protects them by activating NF-κB through Janus kinase 2 (Jak2).

NF-κB transcription factors are critical regulators of apoptosis, and are themselves controlled by the inhibitor of NF-κB (IκB) proteins. Extracellular signals — including those emanating from cytokines — induce the phosphorylation (and hence degradation) of IκBs, allowing NF-κB dimers to enter the nucleus and activate gene transcription.

Studies have shown that NF-κB promotes cell survival through the transcriptional activation of anti-apoptotic genes. Expression of NF-κB in the brain is strongly induced after stress, leading Digicaylioglu and Lipton to investigate whether the anti-apoptotic function of erythropoietin is mediated through NF-κB. Biochemical assays revealed that treatment of neurons with erythropoietin resulted in sustained activation of NF-κB, leading to its translocation into the nucleus followed by DNA binding. As expected, inhibition of NF-κB inhibited the protection.

In non-neuronal cells, binding of erythropoietin to its receptor triggers activation of several intracellular signalling cascades — including phosphorylation of Jak2. The authors extended these observations to neurons and found that interactions between erythropoietin and its receptor also trigger Jak2 phosphorylation. So is Jak2 signalling necessary for NF-κB activation? Expression of a kinase-dead version of Jak2 completely abrogated the anti-apoptotic effect of erythropoietin by preventing the activation of NF-κB. This was specific, as co-transfection with wild-type Jak2 reversed the NF-κB inhibition. An in vitro kinase assay directly showed that Jak2 could phosphorylate IκB inhibitors, leading to the activation of NF-κB.

Numerous studies indicate that NF-κB protects cells from death by transcriptionally activating genes, the products of which block apoptosis. Extrapolating from this, Digicaylioglu and Lipton show that pre-incubation of neurons with erythropoietin increases the expression of inhibitor-of-apoptosis gene products, XIAP and cIAP2. These results indicate that erythropoietin can regulate NF-κB activity through Jak2 signalling, leading to neuroprotection.

This study neatly ties two signalling pathways — Jak2 and NF-κB — together in erythropoietin-stimulated neurons. So why doesn't erythropoietin activate NF-κB in non-neuronal cells? As NF-κB transcription factors are expressed ubiquitously, it is important to find out whether additional neural-specific components are required for this pathway in vivo, and we now need to discover whether recombinant erythropoietin or its mimics can be used for the treatment of neurodegenerative disorders.