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Genetic deletion of an instability motif in the Tristetraprolin (TTP) transcript increases TTP mRNA stability and protein expression and provides protection against inflammatory diseases
Author(s) -
Patial Sonika,
Blackshear Perry
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.711.15
Subject(s) - tristetraprolin , messenger rna , untranslated region , microbiology and biotechnology , tumor necrosis factor alpha , inflammation , three prime untranslated region , chemistry , biology , immunology , gene , genetics
Objective Tristetraprolin (TTP) is an mRNA binding protein that binds to AU‐rich elements (AREs) in the 3′‐untranslated regions (3′UTR) of specific mRNAs, such as tumor necrosis factor (TNF) mRNA, and increases their rates of deadenylation and turnover. TTP mRNA also contains AREs within its own 3′UTR that are partly responsible for its own instability. The objective of this study was to test the hypothesis that increased TTP mRNA stability, and the resulting increased TTP protein expression, may provide protection against inflammatory diseases. Results Using knock‐in technology, a novel TTP mouse line (TTPΔARE) was generated in which 136 bases in the 3′UTR AU‐rich region of TTP mRNA were deleted. TTPΔARE mice developed and reproduced normally, and exhibited no phenotypic or histopathological abnormalities. TTP mRNA stability was found to be significantly enhanced in bone marrow‐derived macrophages (BMDMs) and mouse embryonic fibroblasts (MEFs) isolated from TTPΔARE mice. Moreover, TTP protein expression was increased in unstimulated and LPS‐stimulated BMDMs, and in various mouse tissues. In addition, LPS‐induced expression of TTP target mRNAs, particularly TNF and Il‐1β mRNAs, was significantly reduced in TTPΔARE BMDMs. TTPΔARE mice exhibited reduced skin inflammation in an experimental model of psoriasis, and were completely protected from collagen antibody‐induced arthritis. Conclusions Our data demonstrate that modestly increased levels of TTP in mouse cells and tissues are protective against certain inflammatory disease models. These data may have implications for the development of therapeutic strategies to target chronic inflammatory diseases via enhancing TTP expression.