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.
Ray
Partho Sarothi
PS
Department of Cell Biology, The Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Fox
Paul L
PL
D020413:3' Untranslated Regions / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D002417:Cattle; D005786:Gene Expression Regulation / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D008969:Molecular Sequence Data; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D009690:Nucleic Acid Conformation / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism*
D020413:3' Untranslated Regions; D012333:RNA, Messenger; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D007371:Interferon-gamma