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

Monocyte-macrophage activation by interferon (IFN)-gamma 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-gamma 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-gamma-activated inhibitor of translation (GAIT) complex by bioinformatic analysis, and experimentally validated by messenger RNA-protein interaction studies. Although IFN-gamma 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-gamma-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.