Translational Regulation of Specific mRNAs Controls Feedback Inhibition and Survival during Macrophage Activation


When macrophages encounter pathogens, they initiate inflammation by secreting pro-inflammatory factors such as the cytokine TNF. Because a prolonged or overshooting release of these factors is harmful for the organism, their production needs to be tightly controlled and shut off in due time. To ensure a rapid but transient inflammatory response, gene expression is regulated at multiple levels, including transcription, stability and translation of mRNAs. While control of transcription and mRNA stability has been studied extensively, little is known about translational regulation in macrophages. In this study, we measured the translation of all mRNAs expressed in mouse macrophages. Upon activation of macrophages with the bacterial cell wall component lipopolysaccharide, we found that many feedback inhibitors, which are important for dampening the inflammatory response, are translationally up-regulated. Translation of these mRNAs is repressed in resting cells and de-repressed after stimulation. In contrast to feedback inhibitors, most cytokines are primarily regulated by changes in mRNA abundance. Furthermore, we could show that one of the feedback inhibitors, IER3, protects macrophages from cell death during activation. Therefore, regulation at the level of translation is important for the induction of negative feedback loops and cellular survival.


Vyšlo v časopise: Translational Regulation of Specific mRNAs Controls Feedback Inhibition and Survival during Macrophage Activation. PLoS Genet 10(6): e32767. doi:10.1371/journal.pgen.1004368
Kategorie: Research Article
prolekare.web.journal.doi_sk: 10.1371/journal.pgen.1004368

Souhrn

When macrophages encounter pathogens, they initiate inflammation by secreting pro-inflammatory factors such as the cytokine TNF. Because a prolonged or overshooting release of these factors is harmful for the organism, their production needs to be tightly controlled and shut off in due time. To ensure a rapid but transient inflammatory response, gene expression is regulated at multiple levels, including transcription, stability and translation of mRNAs. While control of transcription and mRNA stability has been studied extensively, little is known about translational regulation in macrophages. In this study, we measured the translation of all mRNAs expressed in mouse macrophages. Upon activation of macrophages with the bacterial cell wall component lipopolysaccharide, we found that many feedback inhibitors, which are important for dampening the inflammatory response, are translationally up-regulated. Translation of these mRNAs is repressed in resting cells and de-repressed after stimulation. In contrast to feedback inhibitors, most cytokines are primarily regulated by changes in mRNA abundance. Furthermore, we could show that one of the feedback inhibitors, IER3, protects macrophages from cell death during activation. Therefore, regulation at the level of translation is important for the induction of negative feedback loops and cellular survival.


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Genetika Reprodukčná medicína

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