Molecular Systems Biology | |
Tristetraprolin‐driven regulatory circuit controls quality and timing of mRNA decay in inflammation | |
Franz Kratochvill4  Christian Machacek4  Claus Vogl1  Florian Ebner4  Vitaly Sedlyarov4  Andreas R Gruber2  Harald Hartweger4  Raimund Vielnascher1  Marina Karaghiosoff1  Thomas Rülicke3  Mathias Müller1  Ivo Hofacker2  Roland Lang5  | |
[1] Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria;Department of Theoretical Chemistry, University of Vienna, Vienna, Austria;Institute of Laboratory Animal Science and Biomodels Austria, University of Veterinary Medicine Vienna, Vienna, Austria;Max F. Perutz Laboratories, Center for Molecular Biology, University of Vienna, Vienna, Austria;Institute of Clinical Microbiology, Immunology and Hygiene, University Hospital Erlangen, Erlangen, Germany | |
关键词: immune homeostasis; inflammation; mRNA stability; p38 MAPK; tristetraprolin; | |
DOI : 10.1038/msb.2011.93 | |
来源: Wiley | |
【 摘 要 】
For a successful yet controlled immune response, cells need to specifically destabilize inflammatory mRNAs but prevent premature removal of those still used. The regulatory circuits controlling quality and timing in the global inflammatory mRNA decay are not understood. Here, we show that the mRNA-destabilizing function of the AU-rich element-binding protein tristetraprolin (TTP) is inversely regulated by the p38 MAPK activity profile such that after inflammatory stimulus the TTP-dependent decay is initially limited to few mRNAs. With time, the TTP-dependent decay gradually spreads resulting in cumulative elimination of one third of inflammation-induced unstable mRNAs in macrophages in vitro. We confirmed this sequential decay model in vivo since LPS-treated mice with myeloid TTP ablation exhibited similar cytokine dysregulation profile as macrophages. The mice were hypersensitive to LPS but otherwise healthy with no signs of hyperinflammation seen in conventional TTP knockout mice demonstrating the requirement for myeloid TTP in re-installment but not maintenance of immune homeostasis. These findings reveal a TTP- and p38 MAPK-dominated regulatory mechanism that is vital for balancing acute inflammation by a temporally and qualitatively controlled mRNA decay. Inflammatory gene activation must be rigorously controlled to ensure a rapid, but transient, response. In this work, a regulatory circuit is revealed that governs the destabilization of inflammatory mRNAs and plays an essential role in re-establishing immune homeostasis after inflammatory stimulus.Abstract
Synopsis
【 授权许可】
CC BY-NC-SA
Copyright © 2011 EMBO and Macmillan Publishers Limited
Creative Commons Attribution License, which permits distribution, and reproduction in any medium, provided the original author and source are credited. This license does not permit commercial exploitation without specific permission.
【 预 览 】
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