Erythropoietin selectively attenuates cytokine production and inflammation in cerebral ischemia by targeting neuronal apoptosis

Ischemic brain injury resulting from stroke arises from primary neuronal losses and by inflammatory responses. Previous studies suggest that erythropoietin (EPO) attenuates both processes. Although EPO is clearly antiapoptotic for neurons after experimental stroke, it is unknown whether EPO also dir...

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Published in:The Journal of experimental medicine 2003-09, Vol.198 (6), p.971-975
Main Authors: Villa, Pia, Bigini, Paolo, Mennini, Tiziana, Agnello, Davide, Laragione, Teresa, Cagnotto, Alfredo, Viviani, Barbara, Marinovich, Marina, Cerami, Anthony, Coleman, Thomas R, Brines, Michael, Ghezzi, Pietro
Format: Article
Language:English
Subjects:
Animals
Apoptosis - immunology
Apoptosis - physiology
Brain Ischemia - immunology
Brain Ischemia - metabolism
Brief Definitive Report
Cells, Cultured
Coculture Techniques
Cytokines - biosynthesis
Erythropoietin - pharmacology
Erythropoietin - physiology
Humans
Infarction, Middle Cerebral Artery
Inflammation - immunology
Inflammation - metabolism
Lipopolysaccharides - pharmacology
Male
Neuroglia - cytology
Neuroglia - drug effects
Neuroglia - metabolism
Neurons - cytology
Neurons - metabolism
Neuroprotective Agents - metabolism
Rats
Receptors, Erythropoietin - metabolism
Recombinant Proteins - pharmacology
Tumor Necrosis Factor-alpha - metabolism
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Summary:Ischemic brain injury resulting from stroke arises from primary neuronal losses and by inflammatory responses. Previous studies suggest that erythropoietin (EPO) attenuates both processes. Although EPO is clearly antiapoptotic for neurons after experimental stroke, it is unknown whether EPO also directly modulates EPO receptor (EPO-R)-expressing glia, microglia, and other inflammatory cells. In these experiments, we show that recombinant human EPO (rhEPO; 5,000 U/kg body weight, i.p.) markedly reduces astrocyte activation and the recruitment of leukocytes and microglia into an infarction produced by middle cerebral artery occlusion in rats. In addition, ischemia-induced production of the proinflammatory cytokines tumor necrosis factor, interleukin 6, and monocyte chemoattractant protein 1 concentration is reduced by >50% after rhEPO administration. Similar results were also observed in mixed neuronal-glial cocultures exposed to the neuronal-selective toxin trimethyl tin. In contrast, rhEPO did not inhibit cytokine production by astrocyte cultures exposed to neuronal homogenates or modulate the response of human peripheral blood mononuclear cells, rat glial cells, or the brain to lipopolysaccharide. These findings suggest that rhEPO attenuates ischemia-induced inflammation by reducing neuronal death rather than by direct effects upon EPO-R-expressing inflammatory cells.
ISSN:0022-1007
1540-9538
DOI:10.1084/jem.20021067