title: Dominant Suppression of Inflammation via Targeted Mutation of the mRNA Destabilizing Protein Tristetraprolin.
abstract: In myeloid cells, the mRNA-destabilizing protein tristetraprolin (TTP) is induced and extensively phosphorylated in response to LPS. To investigate the role of two specific phosphorylations, at serines 52 and 178, we created a mouse strain in which those residues were replaced by nonphosphorylatable alanine residues. The mutant form of TTP was constitutively degraded by the proteasome and therefore expressed at low levels, yet it functioned as a potent mRNA destabilizing factor and inhibitor of the expression of many inflammatory mediators. Mice expressing only the mutant form of TTP were healthy and fertile, and their systemic inflammatory responses to LPS were strongly attenuated. Adaptive immune responses and protection against infection by Salmonella typhimurium were spared. A single allele encoding the mutant form of TTP was sufficient for enhanced mRNA degradation and underexpression of inflammatory mediators. Therefore, the equilibrium between unphosphorylated and phosphorylated TTP is a critical determinant of the inflammatory response, and manipulation of this equilibrium may be a means of treating inflammatory pathologies.
authors.affiliation: School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom;
authors.forename: Ewan A
authors.initials: EA
authors.lastname: Ross
authors.affiliation: School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom;
authors.forename: Tim
authors.initials: T
authors.lastname: Smallie
authors.affiliation: Imperial College London, Hammersmith Hospital, London W12 0NN, United Kingdom;
authors.forename: Qize
authors.initials: Q
authors.lastname: Ding
authors.affiliation: School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom;
authors.forename: John D
authors.initials: JD
authors.lastname: O'Neil
authors.affiliation: School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom;
authors.forename: Helen E
authors.initials: HE
authors.lastname: Cunliffe
authors.affiliation: School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom;
authors.forename: Tina
authors.initials: T
authors.lastname: Tang
authors.affiliation: School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom;
authors.forename: Dalya R
authors.initials: DR
authors.lastname: Rosner
authors.affiliation: Unit of Signal Transduction, Interdisciplinary Cluster for Applied Genoproteomics, University of Liege, University Hospital, 4000 Liege, Belgium;
authors.forename: Iva
authors.initials: I
authors.lastname: Klevernic
authors.affiliation: Beatson Institute for Cancer Research, Bearsden, Glasgow G61 1BD, United Kingdom; and.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Morrice
authors.affiliation: Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7FY, United Kingdom.
authors.forename: Claudia
authors.initials: C
authors.lastname: Monaco
authors.affiliation: School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom;
authors.forename: Adam F
authors.initials: AF
authors.lastname: Cunningham
authors.affiliation: School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom;
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Buckley
authors.affiliation: Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7FY, United Kingdom.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Saklatvala
authors.affiliation: Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7FY, United Kingdom.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Dean
authors.affiliation: School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom; a.r.clark@bham.ac.uk.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Clark
mesh_terms: D000409:Alanine / Q000235:genetics / Q000378:metabolism; D019943:Amino Acid Substitution; D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D005260:Female; D015870:Gene Expression; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D010750:Phosphoproteins / Q000235:genetics / Q000276:immunology; D010766:Phosphorylation; D061251:Primary Cell Culture; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D012481:Salmonella Infections, Animal / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D012486:Salmonella typhimurium / Q000276:immunology; D012694:Serine / Q000235:genetics / Q000378:metabolism; D051816:Tristetraprolin / Q000235:genetics / Q000276:immunology*
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D010750:Phosphoproteins; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D051816:Tristetraprolin; C497553:Zfp36 protein, mouse; D012694:Serine; D000409:Alanine