Erythropoietin does not attenuate cytokine production and inflammation in microglia — Implications for the neuroprotective effect of erythropoietin in neurological diseases
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Abstract
Erythropoietin is a hematopoietic cytokine which is also produced in the brain under
hypoxia. Since this pathology is associated with glial cell activation and release
of cytotoxic molecules, we investigated the expression of EPO receptors (EPO-R) and
effects of erythropoietin on microglial cell functions in vitro using RT-PCR, Western
immunoblotting, nitric oxide measurement, tumor necrosis factor-alpha-(TNF-alpha)-ELISA
and gel shift assay analyses. Furthermore, we examined if erythropoietin could modulate
proliferation of microglia. As shown by reverse transcription-polymerase chain reaction
and immunocytochemistry, rat microglial cells and the murine microglia cell line BV-2
express the EPO-R. However, EPO showed no effect on the release of the proinflammatory
mediators' nitric oxide and TNF-alpha. Moreover, EPO was not able to reduce the LPS
(lipopolysaccharide) stimulated translocation of the proinflammatory transcription
factor NF-kappaB into the nucleus of murine microglia, but induced (3)H-thymidine
incorporation into DNA of microglial cells. These results show that microglia are
target cells for erythropoietin which possesses mitogenic, but not anti-inflammatory
effects on microglia. Therefore, the well-documented neuroprotective effects of erythropoietin
could not be ascribed to an anti-inflammatory effect on microglia.