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

Pia Villa, Paolo Bigini, Tiziana Mennini, Davide Agnello, Teresa Laragione, Alfredo Cagnotto, Barbara Viviani, Marina Marinovich, Anthony Cerami, Thomas R. Coleman, Michael Brines, Pietro Ghezzi

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)971-975
Number of pages5
JournalJournal of Experimental Medicine
Volume198
Issue number6
DOIs
Publication statusPublished - Sep 15 2003

Keywords

  • Apoptosis
  • Erythropoietin
  • Inflammation
  • Ischemia
  • Stroke

ASJC Scopus subject areas

  • Immunology

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