AUTHOR=Sneezum Lucy , Eislmayr Kevin , Dworak Helene , Sedlyarov Vitaly , Le Heron Anita , Ebner Florian , Fischer Irmgard , Iwakura Yoichiro , Kovarik Pavel 

TITLE=Context-Dependent IL-1 mRNA-Destabilization by TTP Prevents Dysregulation of Immune Homeostasis Under Steady State Conditions

JOURNAL=Frontiers in Immunology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.01398

DOI=10.3389/fimmu.2020.01398

ISSN=1664-3224

ABSTRACT=<p>The bioavailability of the major pro-inflammatory cytokines IL-1α and IL-1β is tightly controlled by transcription and post-translational processing to prevent hyperinflammation. The role of mRNA decay in maintenance of physiological IL-1 amounts remained unknown. Here we show that the down-regulation of <italic>Il1a</italic> and <italic>Il1b</italic> mRNA by the mRNA-destabilizing protein TTP (gene <italic>Zfp36</italic>) is required for immune homeostasis. The TTP deficiency syndrome, a multi organ inflammation in <italic>TTP</italic><sup>−/−</sup> mice, was significantly ameliorated upon deletion of the IL-1 receptor. <italic>Il1a</italic> and <italic>Il1b</italic> played non-redundant roles in triggering the pathological IL-1 signaling in <italic>TTP</italic><sup>−/−</sup> mice. Accordingly, tissues from <italic>TTP</italic><sup>−/−</sup> animals contained increased amounts of <italic>Il1b</italic> mRNA. Unexpectedly, TTP destabilized <italic>Il1b</italic> mRNA in cell type-specific ways as evident from RNA-Seq and mRNA stability assays. These results demonstrate that TTP-driven mRNA destabilization depends on the cellular context. Moreover, such context-defined mRNA decay is essential for keeping steady state IL-1 levels in the physiological range.</p>