Endogenous erythropoietin as part of the cytokine network in the pathogenesis of experimental autoimmune encephalomyelitis.
Erythropoietin (EPO) is of great interest as a therapy for many of the central nervous system (CNS) diseases and its administration is protective in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Endogenous EPO is induced by hypoxic/ischemic injury, but little is known about its expression in other CNS diseases. We report here that EPO expression in the spinal cord is induced in mouse models of chronic or relapsing-remitting EAE, and is prominently localized to motoneurons. We found a parallel increase of hypoxia-inducible transcription factor (HIF)-1 alpha, but not HIF-2 alpha, at the mRNA level, suggesting a possible role of non-hypoxic factors in EPO induction. EPO mRNA in the spinal cord was co-expressed with interferon (IFN)-gamma and tumor necrosis factor (TNF), and these cytokines inhibited EPO production in vitro in both neuronal and glial cells. Given the known inhibitory effect of EPO on neuroinflammation, our study indicates that EPO should be viewed as part of the inflammatory/anti-inflammatory network in MS.
Mengozzi
Manuela
M
Mario Negri Institute for Pharmacological Research, Milan, Italy.
Cervellini
Ilaria
I
Bigini
Paolo
P
Martone
Sara
S
Biondi
Antonella
A
Pedotti
Rosetta
R
Gallo
Barbara
B
Barbera
Sara
S
Mennini
Tiziana
T
Boraso
Mariaserena
M
Marinovich
Marina
M
Petit
Edwige
E
Bernaudin
Myriam
M
Bianchi
Roberto
R
Viviani
Barbara
B
Ghezzi
Pietro
P
D000818:Animals; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism*; D004921:Erythropoietin / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000494:pharmacology; D051379:Mice; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013116:Spinal Cord / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D016207:Cytokines; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014409:Tumor Necrosis Factor-alpha; D004921:Erythropoietin; D007371:Interferon-gamma