ZO-1 expression is suppressed by GM-CSF via miR-96/ERG in brain microvascular endothelial cells

Abstract

The level of granulocyte-macrophage colony-stimulating factor (GM-CSF) increases in some disorders such as vascular dementia, Alzheimer's disease, and multiple sclerosis. We previously reported that in Alzheimer's disease patients, a high level of GM-CSF in the brain parenchyma downregulated expression of ZO-1, a blood-brain barrier tight junction protein, and facilitated the infiltration of peripheral monocytes across the blood-brain barrier. However, the molecular mechanism underlying regulation of ZO-1 expression by GM-CSF is unclear. Herein, we found that the erythroblast transformation-specific (ETS) transcription factor ERG cooperated with the proto-oncogene protein c-MYC in regulation of ZO-1 transcription in brain microvascular endothelial cells (BMECs). The ERG expression was suppressed by miR-96 which was increased by GM-CSF through the phosphoinositide-3 kinase (PI3K)/Akt pathway. Inhibition of miR-96 prevented ZO-1 down-regulation induced by GM-CSF both in vitro and in vivo. Our results revealed the mechanism of ZO-1 expression reduced by GM-CSF, and provided a potential target, miR-96, which could block ZO-1 down-regulation caused by GM-CSF in BMECs.

Inter-Tumor Heterogeneity—Melanomas Respond Differently to GM-CSF-Mediated Activation

“…TJs regulate permeability of the blood-brain barrier (BBB) [ 31 ]. In light of findings that GM-CSF modulates TJ components claudin-5 [ 32 ] and zonula occludens-1 (ZO-1) [ 33 ] thereby altering transendothelial migration of mouse monocytes, we asked if human GM-CSF would also induce similar effects in human brain endothelial cells. rhGM-CSF was added to cultured BEC for 2, 6, 24 and 48 h. A significant decrease in claudin-5 levels in GM-CSF treated BEC was observed 24 and 48 h post stimulation ( Figure 1 c).…”

Roles of GM-CSF in the Pathogenesis of Autoimmune Diseases: An Update

“…Shang et al have indicated that GM-CSF down-regulates the expression of ZO-1 and claudin-5 in HBMECs, which induces the disruption of tight junctions in BBB (46). Additionally, in another study, intracerebroventricular injection of GM-CSF to wild-type mice was accompanied by a decrease in ZO-1expression in comparison to the PBS group (47) (Figure 1).…”

Bone morphogenetic protein signaling is required for RAD51-mediated maintenance of genome integrity in vascular endothelial cells

“…The inhibition of miR-96 has also been shown to be critical in the context of the pathogenesis of Alzheimer’s disease, according to a study performed in brain microvascular endothelial cells in response to granulocyte-macrophage colony-stimulating factor 48 . Furthermore, miR-96 -mediated downregulation of RAD51 in cancer cell lines increases their sensitivity to chemotherapy agents and leads to cell death 35 , a result similar to our observations in pulmonary microvascular endothelial cells upon inhibition of bone morphogenetic protein signaling.…”