title: Molecular mechanism of Jmjd3-mediated interleukin-6 gene regulation in endothelial cells underlying spinal cord injury.
abstract: The inflammatory response contributes substantially to secondary injury cascades after spinal cord injury, with both neurotoxic and protective effects. However, epigenetic regulations of inflammatory genes following spinal cord injury have yet to be characterized thoroughly. In this study, we found that histone H3K27me3 demethylase Jmjd3 expression is acutely up-regulated in blood vessels of the injured spinal cord. We also observed up-regulation of Jmjd3 gene expression in bEnd.3 endothelial cells that were subjected to oxygen-glucose deprivation/reperfusion injury. When Jmjd3 was depleted by siRNA, oxygen-glucose deprivation/reperfusion injury-induced up-regulation of IL-6 was significantly inhibited. In addition, Jmjd3 associated with NF-κB (p65/p50) and CCAAT-enhancer-binding protein β at the IL-6 gene promoter. The recruitment of Jmjd3 coincided with decreased levels of tri-methylated H3K27 as well as increased levels of mono-methylated H3K27 at the IL-6 gene promoter. Furthermore, Jmjd3 depletion did not result in significant changes of methylation level of H3K27 at the IL-6 gene promoter. Collectively, our findings imply that Jmjd3-mediated H3K27me3 demethylation is crucial for IL-6 gene activation in endothelial cells, and this molecular event may regulate acute inflammatory response and integrity of the blood-spinal cord barrier following spinal cord injury.
authors.affiliation: Department of Life Science, Sogang University, Seoul, Korea.
authors.forename: Kwanghyun
authors.initials: K
authors.lastname: Lee
authors.forename: Wonho
authors.initials: W
authors.lastname: Na
authors.forename: Jee Youn
authors.initials: JY
authors.lastname: Lee
authors.forename: Jungtae
authors.initials: J
authors.lastname: Na
authors.forename: Heejung
authors.initials: H
authors.lastname: Cho
authors.forename: Hongjin
authors.initials: H
authors.lastname: Wu
authors.forename: Tae Young
authors.initials: TY
authors.lastname: Yune
authors.forename: Won-Sun
authors.initials: WS
authors.lastname: Kim
authors.forename: Bong-Gun
authors.initials: BG
authors.lastname: Ju
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000378:metabolism; D015687:Cell Hypoxia / Q000502:physiology; D002478:Cells, Cultured; D019175:DNA Methylation; D042783:Endothelial Cells / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000502:physiology; D005947:Glucose / Q000172:deficiency; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D007249:Inflammation / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics*; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics* / Q000502:physiology*; D008297:Male; D016133:Polymerase Chain Reaction; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000235:genetics / Q000473:pathology; D013119:Spinal Cord Injuries / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D015850:Interleukin-6; D012313:RNA; D056484:Jumonji Domain-Containing Histone Demethylases; C000655037:Kdm6b protein, rat; D005947:Glucose