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UBC Theses and Dissertations

The role of the macrophage migration inhibitory factor in stroke Zis, Odysseas Takis


The macrophage migration inhibitory factor (MIF) is a 12kDa cytokine with pro-inflammatory properties. Initially characterized as a lymphocyte-secreted factor which inhibits macrophage migration in vitro, MIF has emerged as a multi-faceted cytokine involved in many processes, including cellular responses to ischemia/reperfusion injury in the heart. The main objective of this thesis was to determine whether human MIF expression is induced following cerebral ischemia, the underlying mechanism by which MIF expression is regulated under stroke conditions and its role therein. Previous studies have shown that MIF expression and release from cells is induced during hypoxia. However, the underlying mechanism is not clear. 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. The presence of a functional HIF-1α binding site was demonstrated using an electrophoretic mobility shift assay (EMSA). The results showed that upregulation of MIF gene expression under stroke is mediated by the effect of hypoxia on an HRE in MIF gene promoter. MIF has been shown to protect cells from ischemia and oxidative stress-induced cell death. To determine whether MIF has a similar protective effect on neurons, rat primary cortical neurons were cultured and subjected to either oxygen-glucose deprivation or treatment with hydrogen peroxide. MIF significantly reduced both OGD and H2O2-induced cell death. The expression of MIF in human brain has not been characterized. To determine whether the expression of MIF in human brain is altered following ischemia, brain sections from 10 stroke patients were immunostained with an antibody against MIF. Blood vessel endothelial cells in the peri-infarct region of ischemic brain displayed strong MIF immunoreactivity. Normal brain endothelium showed no MIF immunoreactivity. To understand the consequence of increased MIF expression by endothelial cells following stroke, the adhesion of human monocytes to human brain endothelial cells exposed to MIF was evaluated in vitro. MIF suppressed the monocyte adhesion to endothelial cells. The findings presented here are the first to suggest a role for MIF in cerebral ischemia.

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