Journal Article

A Neuroprotective Function for the Hematopoietic Protein Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF)

Gassler, Nikolaus, Dittgen, Tanjew, Krüger, Carola, Kirsch, Friederike, Schneider, Armin, Schäbitz, Wolf-Rüdiger, Laage, Rico, Mier, Walter, Weber, Daniela, Pitzer, Claudia, Sommer, Clemens, Aronowski, Jaroslaw, Bach, Alfred

2008

Overview

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 α-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.

• Publisher: SAGE Publications,Lippincott Williams & Wilkins,Sage Publications Ltd
• Subject: Animals / Apoptosis - drug effects / bcl-X Protein - biosynthesis / Biological and medical sciences / Blood-Brain Barrier - metabolism / Blood-Brain Barrier - pathology / Brain Infarction - drug therapy / Brain Infarction - metabolism / Brain Infarction - pathology / Brain Ischemia - drug therapy / Brain Ischemia - metabolism / Brain Ischemia - pathology / Cell Differentiation - drug effects / Cell Proliferation - drug effects / Cerebral Cortex - metabolism / Cerebral Cortex - pathology / Disease Models, Animal / Dose-Response Relationship, Drug / Drug Evaluation, Preclinical / Granulocyte-Macrophage Colony-Stimulating Factor - pharmacology / Humans / Male / Medical sciences / Myeloid Cells - metabolism / Myeloid Cells - pathology / Neurodegenerative Diseases - drug therapy / Neurodegenerative Diseases - metabolism / Neurodegenerative Diseases - pathology / Neurology / Neurons - metabolism / Neurons - pathology / Neuropharmacology / Neuroprotective agent / Neuroprotective Agents - pharmacology / Pharmacology. Drug treatments / Phosphatidylinositol 3-Kinases - metabolism / Proto-Oncogene Proteins c-akt - metabolism / Rats / Rats, Long-Evans / Rats, Wistar / Receptors, Granulocyte-Macrophage Colony-Stimulating Factor - biosynthesis / Signal Transduction - drug effects / Time Factors / Up-Regulation - drug effects / Vascular diseases and vascular malformations of the nervous system