A neuroprotective function for the hematopoietic protein granulocyte-macrophage colony stimulating factor (GM-CSF).
Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a hematopoietic cytokine responsible for the proliferation, differentiation, and maturation of cells of the myeloid lineage, which was cloned more than 20 years ago. Here we uncovered a novel function of GM-CSF in the central nervous system (CNS). We identified the GM-CSF alpha-receptor as an upregulated gene in a screen for ischemia-induced genes in the cortex. This receptor is broadly expressed on neurons throughout the brain together with its ligand and induced by ischemic insults. In primary cortical neurons and human neuroblastoma cells, GM-CSF counteracts programmed cell death and induces BCL-2 and BCL-Xl expression in a dose- and time-dependent manner. Of the signaling pathways studied, GM-CSF most prominently induced the PI3K-Akt pathway, and inhibition of Akt strongly decreased antiapoptotic activity. Intravenously given GM-CSF passes the blood-brain barrier, and decreases infarct damage in two different experimental stroke models (middle cerebral artery occlusion (MCAO), and combined common carotid/distal MCA occlusion) concomitant with induction of BCL-Xl expression. Thus, GM-CSF acts as a neuroprotective protein in the CNS. This finding is remarkably reminiscent of the recently discovered functionality of two other hematopoietic factors, erythropoietin and granulocyte colony-stimulating factor in the CNS. The identification of a third hematopoietic factor acting as a neurotrophic factor in the CNS suggests a common principle in the functional evolution of these factors. Clinically, GM-CSF now broadens the repertoire of hematopoietic factors available as novel drug candidates for stroke and neurodegenerative diseases.
Schäbitz
Wolf-Rüdiger
WR
Department of Neurology, University of Münster, Münster, Germany.
Krüger
Carola
C
Pitzer
Claudia
C
Weber
Daniela
D
Laage
Rico
R
Gassler
Nikolaus
N
Aronowski
Jaroslaw
J
Mier
Walter
W
Kirsch
Friederike
F
Dittgen
Tanjew
T
Bach
Alfred
A
Sommer
Clemens
C
Schneider
Armin
A
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001812:Blood-Brain Barrier / Q000378:metabolism / Q000473:pathology; D020520:Brain Infarction / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D006801:Humans; D008297:Male; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D017208:Rats, Wistar; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects; D051020:bcl-X Protein / Q000096:biosynthesis
C494813:Bcl2l1 protein, rat; D018696:Neuroprotective Agents; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D051020:bcl-X Protein; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt