title: Down-regulation of MIF by NFκB under hypoxia accelerated neuronal loss during stroke.
abstract: Neuronal apoptosis is one of the major causes of poststroke neurological deficits. Inflammation during the acute phase of stroke results in nuclear translocation of NFκB in affected cells in the infarct area. Macrophage migration inhibitory factor (MIF) promotes cardiomyocyte survival in mice following heart ischemia. However, the role of MIF during stroke remains limited. In this study, we showed that MIF expression is down-regulated by 0.75 ± 0.10-fold of the control in the infarct area in the mouse brains. Two functional cis-acing NFκB response elements were identified in the human MIF promoter. Dual activation of hypoxia and NFκB signaling resulted in significant reduction of MIF promoter activity to 0.86 ± 0.01-fold of the control. Furthermore, MIF reduced caspase-3 activation and protected neurons from oxidative stress- and in vitro ischemia/reperfusion-induced apoptosis. H2O2 significantly induced cell death with 12.81 ± 0.58-fold increase of TUNEL-positive cells, and overexpression of MIF blocked the H2O2-induced cell death. Disruption of the MIF gene in MIF-knockout mice resulted in caspase-3 activation, neuronal loss, and increased infarct development during stroke in vivo. The infarct volume was increased from 6.51 ± 0.74% in the wild-type mice to 9.07 ± 0.66% in the MIF-knockout mice. Our study demonstrates that MIF exerts a neuronal protective effect and that down-regulation of MIF by NFκB-mediated signaling under hypoxia accelerates neuronal loss during stroke. Our results suggest that MIF is an important molecule for preserving a longer time window for stroke treatment, and strategies to maintain MIF expression at physiological level could have beneficial effects for stroke patients.
authors: Townsend Family Laboratories, Department of Psychiatry, Brain Research Center, Graduate Program in Neuroscience, The University of British Columbia, Vancouver, British Columbia, Canada;
authors: Si
authors: S
authors: Zhang
authors: Townsend Family Laboratories, Department of Psychiatry, Brain Research Center, Graduate Program in Neuroscience, The University of British Columbia, Vancouver, British Columbia, Canada;
authors: Odysseus
authors: O
authors: Zis
authors: Townsend Family Laboratories, Department of Psychiatry, Brain Research Center, Graduate Program in Neuroscience, The University of British Columbia, Vancouver, British Columbia, Canada;
authors: Philip T T
authors: PT
authors: Ly
authors: Townsend Family Laboratories, Department of Psychiatry, Brain Research Center, Graduate Program in Neuroscience, The University of British Columbia, Vancouver, British Columbia, Canada;
authors: Yili
authors: Y
authors: Wu
authors: Townsend Family Laboratories, Department of Psychiatry, Brain Research Center, Graduate Program in Neuroscience, The University of British Columbia, Vancouver, British Columbia, Canada;
authors: Shuting
authors: S
authors: Zhang
authors: Townsend Family Laboratories, Department of Psychiatry, Brain Research Center, Graduate Program in Neuroscience, The University of British Columbia, Vancouver, British Columbia, Canada;
authors: Mingming
authors: M
authors: Zhang
authors: Townsend Family Laboratories, Department of Psychiatry, Brain Research Center, Graduate Program in Neuroscience, The University of British Columbia, Vancouver, British Columbia, Canada;
authors: Fang
authors: F
authors: Cai
authors: Department of Medicine and Department of Pathology, Yale University, New Haven, Connecticut, USA; and.
authors: Richard
authors: R
authors: Bucala
authors: Department of Neurology, Center for Neuropsychiatry, and Graduate Institute of Immunology, China Medical University and Hospital, Taichung, Taiwan.
authors: Woei-Cherng
authors: WC
authors: Shyu
authors: Townsend Family Laboratories, Department of Psychiatry, Brain Research Center, Graduate Program in Neuroscience, The University of British Columbia, Vancouver, British Columbia, Canada; weihong@mail.ubc.ca.
authors: Weihong
authors: W
authors: Song
mesh_terms: D000818:Animals; D017209:Apoptosis; D015687:Cell Hypoxia; D002478:Cells, Cultured; D015536:Down-Regulation; D057809:HEK293 Cells; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism* / Q000473:pathology; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D018384:Oxidative Stress
chemical_list: D008263:Macrophage Migration-Inhibitory Factors; D016328:NF-kappa B; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse
keywords: caspase-3; macrophage migration inhibitory factor; nuclear factor κB