Endogenous Erythropoietin as Part of the Cytokine Network in the Pathogenesis of Experimental Autoimmune Encephalomyelitis
Erythropoietin (EPO) is of great interest as a therapy for many of the central nervous system (CNS) diseases and its administration is protective in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Endogenous EPO is induced by hypoxic/ischemic injury, but little is known about its expression in other CNS diseases. We report here that EPO expression in the spinal cord is induced in mouse models of chronic or relapsing-remitting EAE, and is prominently localized to motoneurons. We found a parallel increase of hypoxia-inducible transcription factor (HIF)-1α, but not HIF-2α, at the mRNA level, suggesting a possible role of non-hypoxic factors in EPO induction. EPO mRNA in the spinal cord was co-expressed with interferon (IFN)-γ and tumor necrosis factor (TNF), and these cytokines inhibited EPO production in vitro in both neuronal and glialcells. Given the known inhibitory effect of EPO on neuroinflammation, our study indicates that EPO should be viewed as part of the inflammatory/anti-inflammatory network in MS.
This study was supported in part by the Kenneth S Warren Institute, Ossining, NY, the Fondazione CARIPLO, Milan, Italy (to PG), the French Centre National de la Recherche Scientifique (CNRS) and the French Ministère de L’Enseignement Supérieur et de la Recherche (to EP and M Bernaudin).
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