Open AccessTristetraprolin‐driven regulatory circuit controls quality and timing of mRNA decay in inflammation
Author(s) -
Kratochvill Franz,
Machacek Christian,
Vogl Claus,
Ebner Florian,
Sedlyarov Vitaly,
Gruber Andreas R,
Hartweger Harald,
Vielnascher Raimund,
Karaghiosoff Marina,
Rülicke Thomas,
Müller Mathias,
Hofacker Ivo,
Lang Roland,
Kovarik Pavel
Publication year - 2011
Publication title -
molecular systems biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 8.523
H-Index - 148
ISSN - 1744-4292
DOI - 10.1038/msb.2011.93
Subject(s) - tristetraprolin , biology , inflammation , quality (philosophy) , messenger rna , computational biology , microbiology and biotechnology , immunology , genetics , gene , rna binding protein , physics , quantum mechanics
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.