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IL-4 mediated gene expression profiles in vascular endothelial cells

ABSTRACT: Endothelial cell activation and dysfunction underlie many vascular disorders, including atherosclerosis and inflammation. Here, we show that interleukin (IL)-4 markedly induced vascular cell adhesion molecule (VCAM)-1, both in cultured endothelial cells and in the intact endothelium in mice. Combined treatment with IL-4 and tumor necrosis factor (TNF)- alpha resulted in further, sustained induction of VCAM-1 expression. IL-4-mediated induction of VCAM-1 and secondary monocyte adhesion was predominantly regulated by the transcription factor, STAT6. Genome-wide survey of IL-4-mediated STAT6 binding from sequential chromatin-immunoprecipitation with deep-sequencing (ChIP-seq) in endothelial cells revealed regions of transient and sustained transcription factor binding. By combining DNA microarrays and ChIP-seq at the same time points, the majority of IL-4-responsive genes were shown to be STAT6-dependent and associated with direct STAT6 binding to their promoter. IL-4-mediated stable binding of STAT6 led to sustained target gene expression. Moreover, our strategy led to the identification of a novel functionally important STAT6 binding site within -16 kb upstream of the VCAM-1 gene. Taken together, these findings support a critical role for STAT6 in mediating IL-4 signal transduction in endothelial cells. Identification of a novel IL-4-mediated VCAM-1 enhancer may provide a foundation for targeted therapy in vascular disease (ChIP-seq data not submitted to GEO).

ORGANISM(S): Homo sapiens

PROVIDER: GSE28117 | GEO | 2011/05/01

SECONDARY ACCESSION(S): PRJNA139837

REPOSITORIES: GEO

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Project description:The objective of this study was to advance the understanding of how in vivo arterial shear forces affect vascular endothelial gene expression. Complicated blood flow patterns at arterial branches create small regions that experience fluctuations in shear stress at frequencies higher than the heart rate. To assess whether such temporal variations in shear stress can affect endothelial gene expression, a series of in vitro microarray experiments was performed. The effects of three sinusoidal waveforms (1, 2, and 3 Hz) and one physiological waveform were compared to the expression profiles under steady flow. At each frequency, three levels of mean shear stress (0, 7.5, and 15 dyn/cm2) were used. Porcine aortic endothelial cells were exposed for 24 hours to each combination, replicated four times. Following shear exposure, phase contrast images of the cells were acquired, and RNA was extracted for microarray analysis against about 10,000 porcine oligonucleotides. Cell alignment with the flow was positively correlated with mean shear (p < 0.001) and independent of frequency. A two-way ANOVA identified 232 genes that were differentially regulated by frequency. The frequency sensitive genes were clustered to identify groups of genes exhibiting similar frequency responses. The largest response was seen at 2 Hz. At this frequency, several inflammatory molecules were upregulated, including VCAM, CTGF, TGF-beta2, c-jun, and IL-8, indicating a potential endothelial atherosusceptibility at this frequency. Mean shear significantly affected the expression of ~3,000 genes. Purely oscillatory flow (zero mean shear) enhanced the expression of several growth factors and adhesion molecules (E-selectin, VCAM, MCP-1, IL-8, c-jun), relative to non-reversing flow (15 dyn/cm2 mean shear). The 2 Hz upregulation of certain atherogenic molecules such as VCAM, c-jun, and IL-8 was enhanced as the mean shear was reduced. Thus, the inflammatory response evoked at certain frequencies appears to be exacerbated by low, oscillatory shear. Keywords: Shear stress response

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IL-4 mediated gene expression profiles in vascular endothelial cells

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