Hypoxia signaling regulates macrophage migration inhibitory factor (MIF) expression in stroke.
The macrophage migration inhibitory factor (MIF) is a multifaceted cytokine involved in many processes, including cellular responses to ischemia/reperfusion injury in the heart and brain. This study was undertaken to determine whether human MIF expression is induced following cerebral ischemia and its role therein. To examine whether the induction of MIF gene expression was mediated by its transcriptional upregulation, the human MIF gene promoter was cloned and a luciferase assay was used to determine the presence of a hypoxia-responsive region in the human MIF promoter. We found that human MIF promoter activity was significantly upregulated by hypoxia. A functional hypoxia-inducible factor 1α-binding site was identified using an electrophoretic mobility shift assay (EMSA). MIF has a protective effect on cortical neurons under oxygen-glucose deprivation (OGD) treatment. MIF significantly reduced OGD-induced cell death. To determine whether the expression of MIF in the human brain is altered following ischemia, brain sections from 10 stroke patients were examined with an antibody against MIF. Blood vessel endothelial cells in the peri-infarct region of ischemic brain displayed strong MIF immunoreactivity with no MIF immunoreactivity in control brains. Furthermore, we found that treatment of human brain endothelial cells with MIF had no effect on human monocyte adhesion to endothelium. Our study demonstrates that MIF gene expression is altered during stroke and dysregulation of the hypoxia signaling-induced MIF expression plays an important role in neuronal death in stroke.
Townsend Family Laboratories, Department of Psychiatry, Brain Research Center, Graduate Program in Neuroscience, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada.
Odysseus
O
Zis
Si
S
Zhang
Katerina
K
Dorovini-Zis
Lijuan
L
Wang
Weihong
W
Song
D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000473:pathology; D002448:Cell Adhesion; D015687:Cell Hypoxia; D019610:Cytoprotection; D005260:Female; D005947:Glucose / Q000172:deficiency; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000378:metabolism*; D008263:Macrophage Migration-Inhibitory Factors / Q000378:metabolism*; D008969:Molecular Sequence Data; D009000:Monocytes / Q000473:pathology; D009474:Neurons / Q000473:pathology; D018696:Neuroprotective Agents / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D017207:Rats, Sprague-Dawley; D020218:Response Elements / Q000235:genetics; D015398:Signal Transduction; D020521:Stroke / Q000378:metabolism* / Q000473:pathology*; D015533:Transcriptional Activation / Q000235:genetics
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008263:Macrophage Migration-Inhibitory Factors; D018696:Neuroprotective Agents; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human; D005947:Glucose; D010100:Oxygen