A post-transcriptional pathway represses monocyte VEGF-A expression and angiogenic activity

Open Access
Publisher Website
Google Scholar
Abstract
Monocyte‐macrophage activation by interferon (IFN)‐γ is a key initiating event in inflammation. Usually, the macrophage response is self‐limiting and inflammation resolves. Here, we describe a mechanism by which IFN‐γ contributes to inflammation resolution by suppressing expression of vascular endothelial growth factor‐A (VEGF‐A), a macrophage product that stimulates angiogenesis during chronic inflammation and tumorigenesis. VEGF‐A was identified as a candidate target of the IFN‐γ‐activated inhibitor of translation (GAIT) complex by bioinformatic analysis, and experimentally validated by messenger RNA–protein interaction studies. Although IFN‐γ induced persistent VEGF‐A mRNA expression, translation was suppressed by delayed binding of the GAIT complex to a specific element delineated in the 3′UTR. Translational silencing resulted in decreased VEGF‐A synthesis and angiogenic activity. Our results describe a unique anti‐inflammatory pathway in which IFN‐γ‐dependent induction of VEGF‐A mRNA is translationally silenced by the same stimulus, and they suggest the GAIT system directs a post‐transcriptional operon that contributes to inflammation resolution.