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ARTICLES The stability of mRNA influences the temporal order of the induction of genes encoding inflammatory molecules 2009 Nature America Inc All rights reserved Shengli Hao David Baltimore The inflammatory response plays out over time in a reproducible and organized way after an initiating stimulus Here we show that genes activated in cultured mouse fibroblasts in response to the cytokine tumor necrosis factor could be categorized into roughly three groups each with different induction kinetics Although differences in transcription were important in determining the grouping of these genes differences in mRNA stability also exerted a strong influence on the temporal order of gene expression in some cases overriding that of transcriptional control elements Transcripts of mRNA expressed early had abundant AU rich elements in their 3 untranslated regions whereas those expressed later had fewer Thus mRNA stability and transcriptional control two intrinsic characteristics of genes control the kinetics of gene expression induced by proinflammatory cytokines As long ago as the first century BC the inflammatory process was recognized as evolving in stereotyped stages1 No matter what invading organism or tissue injury incites the response the temporal order of inflammatory events is very similar From a cellular point of view neutrophils are the first to arrive at a site of inflammation and they stay for only a short time the first 24 h Monocytes arrive somewhat later but stay for days Tissue remodeling processes take over during the late stages of inflammation2 There are two possibilities for how this stereotypical process could be orchestrated each stage could induce the next or the temporal order of events could be encoded intrinsically in the genes involved in the inflammatory process By analyzing events in cultured cells we have come to realize that much of the time course of the response program is encoded in the genes themselves The sequential order of gene expression



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