The blood-brain barrier (BBB) or blood-spinal cord barrier (BSCB) formed by capillary endothelial cells provides a physical wall between the central nervous system (CNS) and circulating blood with highly selective permeability. BBB/BSCB disruption by activation of matrix metalloproteinases (MMPs) has been shown to result in further neurological damage after CNS injury. Recently, it has been discovered that estrogen attenuates BBB/BSCB disruption in in vitro and in vivo models. However, the molecular mechanism underlying estrogen-mediated attenuation of BBB/BSCB disruption has not been elucidated fully. In the present study, we found that 17β-estradiol (E2) suppresses NF-κB-dependent MMP-1b, MMP-2, MMP-3, MMP-9, MMP-10, and MMP-13 gene activation in microvessel endothelial bEnd.3 cells subjected to oxygen and glucose deprivation/reperfusion injury. E2 induced recruitment of ERα and N-CoR corepressor to the NF-κB binding site on the MMPs’ gene promoters. Consistently, ER antagonist ICI 182,780 showed opposi...

J. Neurochem. (2012) 122, 272–282. 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.

It has been shown that epigenetic regulation plays an important role in skin wound healing. We previously found that histone H3K27me3 demethylase JMJD3 regulates inflammation and cell migration in keratinocyte wound healing. In this study, we identified Notch1 as a direct target of JMJD3 and NF-κB in wounded keratinocytes using in vitro cell and in vivo animal models. We found that Notch1 is up-regulated in the wound edge and its expression is dependent on JMJD3 and NF-κB in wounded keratinocytes. We also found that Notch1 activates the expression of RhoU and PLAU gene, which are critical regulators of cell migration. Consistently, depletion or inactivation of Notch1 resulted in decreased filopodia formation, increased focal adhesion and actin stress fiber, leading to reduced keratinocyte migration and skin wound healing. Thus, our findings provide the molecular mechanism involving JMJD3/NF-κB-Notch pathway in keratinocyte wound healing.