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    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 Il1a and Il1b mRNA by the mRNA-destabilizing protein TTP (gene Zfp36) is required for immune homeostasis. The TTP deficiency syndrome, a multi organ inflammation in TTP -/- mice, was significantly ameliorated upon deletion of the IL-1 receptor. Il1a and Il1b played non-redundant roles in triggering the pathological IL-1 signaling in TTP -/- mice. Accordingly, tissues from TTP -/- animals contained increased amounts of Il1b mRNA. Unexpectedly, TTP destabilized Il1b 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. Copyright © 2020 Sneezum, Eislmayr, Dworak, Sedlyarov, Le Heron, Ebner, Fischer, Iwakura and Kovarik.


    Lucy Sneezum, Kevin Eislmayr, Helene Dworak, Vitaly Sedlyarov, Anita Le Heron, Florian Ebner, Irmgard Fischer, Yoichiro Iwakura, Pavel Kovarik. Context-Dependent IL-1 mRNA-Destabilization by TTP Prevents Dysregulation of Immune Homeostasis Under Steady State Conditions. Frontiers in immunology. 2020;11:1398

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    PMID: 32733464

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