title: Enhanced stability of tristetraprolin mRNA protects mice against immune-mediated inflammatory pathologies.
abstract: Tristetraprolin (TTP) is an inducible, tandem zinc-finger mRNA binding protein that binds to adenylate-uridylate-rich elements (AREs) in the 3'-untranslated regions (3'UTRs) of specific mRNAs, such as that encoding TNF, and increases their rates of deadenylation and turnover. Stabilization of Tnf mRNA and other cytokine transcripts in TTP-deficient mice results in the development of a profound, chronic inflammatory syndrome characterized by polyarticular arthritis, dermatitis, myeloid hyperplasia, and autoimmunity. To address the hypothesis that increasing endogenous levels of TTP in an intact animal might be beneficial in the treatment of inflammatory diseases, we generated a mouse model (TTPΔARE) in which a 136-base instability motif in the 3'UTR of TTP mRNA was deleted in the endogenous genetic locus. These mice appeared normal, but cultured fibroblasts and macrophages derived from them exhibited increased stability of the otherwise highly labile TTP mRNA. This resulted in increased TTP protein expression in LPS-stimulated macrophages and increased levels of TTP protein in mouse tissues. TTPΔARE mice were protected from collagen antibody-induced arthritis, exhibited significantly reduced inflammation in imiquimod-induced dermatitis, and were resistant to induction of experimental autoimmune encephalomyelitis, presumably by dampening the excessive production of proinflammatory mediators in all cases. These data suggest that increased systemic levels of TTP, secondary to increased stability of its mRNA throughout the body, can be protective against inflammatory disease in certain models and might be viewed as an attractive therapeutic target for the treatment of human inflammatory diseases.
authors.affiliation: Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709;
authors.forename: Sonika
authors.initials: S
authors.lastname: Patial
authors.affiliation: Department of Microbiology and Immunology, East Carolina University Brody School of Medicine, Greenville, NC 27858;
authors.forename: Alan D
authors.initials: AD
authors.lastname: Curtis
authors.affiliation: Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709;
authors.forename: Wi S
authors.initials: WS
authors.lastname: Lai
authors.affiliation: Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709;
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Stumpo
authors.affiliation: Integrated Laboratory Systems, Research Triangle Park, NC 27709;
authors.forename: Georgette D
authors.initials: GD
authors.lastname: Hill
authors.affiliation: Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709;
authors.forename: Gordon P
authors.initials: GP
authors.lastname: Flake
authors.affiliation: Department of Microbiology and Immunology, East Carolina University Brody School of Medicine, Greenville, NC 27858;
authors.forename: Mark D
authors.initials: MD
authors.lastname: Mannie
authors.affiliation: Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709; Departments of Medicine and Biochemistry, Duke University Medical Center, Durham, NC 27710 black009@niehs.nih.gov.
authors.forename: Perry J
authors.initials: PJ
authors.lastname: Blackshear
mesh_terms: D000634:Aminoquinolines / Q000009:adverse effects; D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics; D002478:Cells, Cultured; D003094:Collagen / Q000276:immunology; D003872:Dermatitis / Q000209:etiology / Q000235:genetics; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics; D000077271:Imiquimod; D007249:Inflammation / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D012333:RNA, Messenger / Q000235:genetics*; D051816:Tristetraprolin / Q000235:genetics* / Q000378:metabolism
chemical_list: D000634:Aminoquinolines; D012333:RNA, Messenger; D051816:Tristetraprolin; C497553:Zfp36 protein, mouse; D003094:Collagen; D000077271:Imiquimod
keywords: AU-rich elements; deadenylation; inflammation; mRNA stability
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