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 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.
Villa
Pia
P
Mario Negri Institute for Pharmacological Research, 20157, Milan, Italy.
Bigini
Paolo
P
Mennini
Tiziana
T
Agnello
Davide
D
Laragione
Teresa
T
Cagnotto
Alfredo
A
Viviani
Barbara
B
Marinovich
Marina
M
Cerami
Anthony
A
Coleman
Thomas R
TR
Brines
Michael
M
Ghezzi
Pietro
P
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
D016207:Cytokines; D008070:Lipopolysaccharides; D018696:Neuroprotective Agents; D017467:Receptors, Erythropoietin; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D004921:Erythropoietin