Colony stimulating factors (CSF) including interleukin-3, modulate the function of
multiple vascular cell types may contribute to atherosclerosis, by binding to their
respective receptors. However little is known about endothelial cell effects, and
neovascularisation has recently been identified as a pro-atherosclerotic factor. Accordingly
we examined the effects of pro- and anti-inflammatory mediators (TNFα, IFNγ, LPS,
TGFβ and IL-4) on human umbilical vein endothelial cell (HUVEC) expression of CSF
receptors (n=6). Interestingly, QPCR with primers validated in granulocytes/macrophages
demonstrated that G-CSF, M-CSF, or GM-CSF receptor expression was not detected. However,
both subunits of the IL-3 receptor (alpha and beta) were significantly increased by
pro-inflammatory stimuli (TNFα, 20-fold and 7-fold respectively p<0.05; IFNγ, 6-fold
and 5-fold respectively p<0.05). Accordingly addition of IL-3 to TNFα-stimulated HUVECs
activated IL-3 receptor downstream signalling as observed by STAT5 phosphorylation.
Consequently, IL-3 stimulated HUVECs exhibited significantly increased migration (55%,
p<0.05) compared to control cells, which could be retarded in the presence of a STA5
inhibitor. To determine if increased IL-3 signalling matrix metalloproteinases (MMPs)
expression and therefore promotes migration, we assessed the mRNA expression of all
MMPs and tissue inhibitors of MMPs (TIMPs). We detected increased MMP-1, -2, -3, -10
and -25 alongside altered TIMP-2 and -3 expressions. By use of specific inhibitors
or siRNA, we demonstrated that MMP-2, -3 and -10 promote endothelial cell migration.
This study demonstrates that inflammation-induced expression of the IL-3 receptor
on endothelial cells directs their MMP expression and migratory potential, highlighting
IL-3 as a potential regulator of atherosclerotic intraplaque neovascularisation.
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© 2013 Published by Elsevier Inc.