title: Erythropoietin selectively attenuates cytokine production and inflammation in cerebral ischemia by targeting neuronal apoptosis.
abstract: 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.
authors.affiliation: Mario Negri Institute for Pharmacological Research, 20157, Milan, Italy.
authors.forename: Pia
authors.initials: P
authors.lastname: Villa
authors.forename: Paolo
authors.initials: P
authors.lastname: Bigini
authors.forename: Tiziana
authors.initials: T
authors.lastname: Mennini
authors.forename: Davide
authors.initials: D
authors.lastname: Agnello
authors.forename: Teresa
authors.initials: T
authors.lastname: Laragione
authors.forename: Alfredo
authors.initials: A
authors.lastname: Cagnotto
authors.forename: Barbara
authors.initials: B
authors.lastname: Viviani
authors.forename: Marina
authors.initials: M
authors.lastname: Marinovich
authors.forename: Anthony
authors.initials: A
authors.lastname: Cerami
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Coleman
authors.forename: Michael
authors.initials: M
authors.lastname: Brines
authors.forename: Pietro
authors.initials: P
authors.lastname: Ghezzi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology / Q000502:physiology*; D002545:Brain Ischemia / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis*; D004921:Erythropoietin / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D020244:Infarction, Middle Cerebral Artery; D007249:Inflammation / Q000276:immunology / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D009457:Neuroglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000378:metabolism; D051381:Rats; D017467:Receptors, Erythropoietin / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D018696:Neuroprotective Agents; D017467:Receptors, Erythropoietin; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D004921:Erythropoietin