title: Ischemic brain extract increases SDF-1 expression in astrocytes through the CXCR2/miR-223/miR-27b pathway.
abstract: Ischemic cerebral stroke is one of the leading global causes of mortality and morbidity. Ischemic preconditioning (IPC) refers to a sublethal ischemia and resulting in tolerance to subsequent severe ischemic injury. Although several pathways are reportedly involved in IPC-mediated neuroprotection, the functional role of astrocytes is not fully understood. Stromal cell-derived factor-1 (SDF-1), a CXC chemokine produced mainly in astrocytes, is a ligand for chemokine receptor CXCR4. SDF-1 is reported to play a critical role in neuroprotection after stroke by mediating the migration of neuronal progenitor cells. We hypothesized that stimuli derived from ischemic brain were involved in the protective effects of IPC. To investigate this hypothesis, the mechanism in which ischemic brain extract (IBE) induced SDF-1 expression was investigated in C6 astrocytoma cells. IBE treatment of C6 cells increased SDF-1 expression compared to that in untreated or normal brain extract (NBE)-treated cells by downregulating SDF-1 targeting miRNA, miR-27b. MiR-223 was inversely upregulated in IBE-treated cells; overexpression of miR-223 decreased the expression of miR-27b by suppressing IKKα expression. Analysis of cytokine array data revealed an IBE associated enhanced expression of CINC-1 (CXCL1) and LIX1 (CXCL5). Knockdown or inhibition of their receptor, CXCR2, abolished IBE-mediated increased expression of SDF-1. These results were confirmed in primary cultured astrocytes. Taken together, the data demonstrate that IBE-elicited signals increase SDF-1 expression through the CXCR2/miR-223/miR-27b pathway in C6 astrocytoma cells and primary astrocytes, supporting the view that increased expression of SDF-1 by ischemic insults is a possible mechanism underlying therapeutic application of IPC.
authors.affiliation: Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul 135-710, South Korea; Samsung Biomedical Research Institute, Institute for Future Medicine, Samsung Medical Center, Seoul 135-710, South Korea.
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Shin
authors.affiliation: Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul 135-710, South Korea; Samsung Biomedical Research Institute, Institute for Future Medicine, Samsung Medical Center, Seoul 135-710, South Korea.
authors.forename: Young Mi
authors.initials: YM
authors.lastname: Park
authors.affiliation: Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul 135-710, South Korea.
authors.forename: Dong Hee
authors.initials: DH
authors.lastname: Kim
authors.affiliation: Samsung Biomedical Research Institute, Institute for Future Medicine, Samsung Medical Center, Seoul 135-710, South Korea; Medical Research Institute, Sungkyunkwan University School of Medicine, Suwon 440-746, South Korea.
authors.forename: Gyeong Joon
authors.initials: GJ
authors.lastname: Moon
authors.affiliation: Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul 135-710, South Korea; Department of Neurology, Samsung Medical Center, Seoul 135-710, South Korea.
authors.forename: Oh Young
authors.initials: OY
authors.lastname: Bang
authors.affiliation: Department of Cellular and Molecular Medicine, College of Medicine, Chosun University, Gwangju 501-759, South Korea.
authors.forename: Takbum
authors.initials: T
authors.lastname: Ohn
authors.affiliation: Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul 135-710, South Korea; Samsung Biomedical Research Institute, Institute for Future Medicine, Samsung Medical Center, Seoul 135-710, South Korea. Electronic address: hyeonhkim@skku.edu.
authors.forename: Hyeon Ho
authors.initials: HH
authors.lastname: Kim
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000235:genetics*; D051550:I-kappa B Kinase / Q000235:genetics; D019194:Ischemic Preconditioning; D051379:Mice; D035683:MicroRNAs / Q000502:physiology*; D051381:Rats; D023063:Receptors, Interleukin-8B / Q000502:physiology*
chemical_list: D054377:Chemokine CXCL12; C544877:MIRN223 microRNA, mouse; D035683:MicroRNAs; C540674:Mirn27 microRNA, mouse; D023063:Receptors, Interleukin-8B; D051550:I-kappa B Kinase
keywords: Astrocytes; CXCR2; Ischemic preconditioning; MicroRNA; SDF-1