Pro-inflammatory up-regulation of interleukin-3 receptor in endothelial cells modulates their migration and associated MMP expression

      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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