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01-04-2019 | Stroke | Original Article

Neuroprotective activity of leukemia inhibitory factor is relayed through myeloid zinc finger-1 in a rat model of stroke

Authors: Stephanie M. Davis, Lisa A. Collier, Elspeth A. Foran, Christopher C. Leonardo, Craig T. Ajmo Jr, Keith R. Pennypacker

Published in: Metabolic Brain Disease | Issue 2/2019

Abstract

The aim of this study was to determine whether leukemia inhibitory factor (LIF) exerts its neuroprotective effects through signal transduction of the transcription factor myeloid zinc finger-1 (MZF-1). According to the hypothesis of this study, MZF-1 mediates LIF-induced neuroprotective signaling during ELVO through increased expression and transcriptional activity. To determine the in vivo role of MZF-1 in LIF-induced neuroprotection, we used Genomatix software was used to MZF-1 sites in the promoter region of the rat superoxide dismutase 3 (SOD3) gene. Stroke was induced via middle cerebral artery occlusion, and animals were administered PBS or 125 μg/kg LIF at 6, 24, and 48 h after the injury. MZF-1 binding activity was measured using electrophoretic mobility shift assay (EMSA) and its expression/localization were determined using western blot and immunohistochemical analysis. To determine whether MZF-1 relays LIF-induced neuroprotection in vitro, primary cultured neurons were subjected to oxygen-glucose deprivation (OGD) after treatment with PBS or LIF. MZF-1 expression was measured in vitro using real time PCR and immunohistochemical staining. Transfection with siRNA was used to determine whether LIF protected cultured neurons against OGD after silencing MZF-1 expression. Four MZF-1 binding sites were identified by Genomatix, and EMSA confirmed in vivo binding activity in brain after MCAO. LIF significantly increased MZF-1 protein levels compared to PBS treatment at 72 h post-MCAO. In vivo nuclear localization of MZF-1 as well as co-localization of SOD3 and MZF-1 was observed in the cortical neurons of LIF-treated rats. Primary cultured neurons treated with LIF had significantly higher levels of MZF-1 mRNA and protein after LIF treatment compared to neurons treated with PBS. Finally, knockdown MZF-1 using siRNA counteracted the neuroprotective effects of LIF in vitro. These data demonstrate that LIF-mediated neuroprotection is dependent upon MZF-1 activity. Furthermore, these findings identify a novel neuroprotective pathway that employs MZF-1, a transcription factor associated with hematopoietic gene expression.

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Title: Neuroprotective activity of leukemia inhibitory factor is relayed through myeloid zinc finger-1 in a rat model of stroke
Authors: Stephanie M. Davis
Lisa A. Collier
Elspeth A. Foran
Christopher C. Leonardo
Craig T. Ajmo Jr
Keith R. Pennypacker
Publication date: 01-04-2019
Publisher: Springer US
Keywords: Stroke
Leukemia
Published in: Metabolic Brain Disease / Issue 2/2019
Print ISSN: 0885-7490
Electronic ISSN: 1573-7365
DOI: https://doi.org/10.1007/s11011-018-0376-2

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Neuroprotective activity of leukemia inhibitory factor is relayed through myeloid zinc finger-1 in a rat model of stroke

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