title: Gain-of-Function Mutation of Tristetraprolin Impairs Negative Feedback Control of MacrophagesIn Vitroyet Has Overwhelmingly Anti-Inflammatory ConsequencesIn Vivo.
abstract: The mRNA-destabilizing factor tristetraprolin (TTP) binds in a sequence-specific manner to the 3' untranslated regions of many proinflammatory mRNAs and recruits complexes of nucleases to promote rapid mRNA turnover. Mice lacking TTP develop a severe, spontaneous inflammatory syndrome characterized by the overexpression of tumor necrosis factor and other inflammatory mediators. However, TTP also employs the same mechanism to inhibit the expression of the potent anti-inflammatory cytokine interleukin 10 (IL-10). Perturbation of TTP function may therefore have mixed effects on inflammatory responses, either increasing or decreasing the expression of proinflammatory factors via direct or indirect mechanisms. We recently described a knock-in mouse strain in which the substitution of 2 amino acids of the endogenous TTP protein renders it constitutively active as an mRNA-destabilizing factor. Here we investigate the impact on the IL-10-mediated anti-inflammatory response. It is shown that the gain-of-function mutation of TTP impairs IL-10-mediated negative feedback control of macrophage functionin vitroHowever, thein vivoeffects of TTP mutation are uniformly anti-inflammatory despite the decreased expression of IL-10.
authors.affiliation: Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: John D
authors.initials: JD
authors.lastname: O'Neil
authors.affiliation: Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Ewan A
authors.initials: EA
authors.lastname: Ross
authors.affiliation: Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Ridley
authors.affiliation: Faculty of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Qize
authors.initials: Q
authors.lastname: Ding
authors.affiliation: Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Tina
authors.initials: T
authors.lastname: Tang
authors.affiliation: Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Dalya R
authors.initials: DR
authors.lastname: Rosner
authors.affiliation: Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Thomas
authors.initials: T
authors.lastname: Crowley
authors.affiliation: Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Deepak
authors.initials: D
authors.lastname: Malhi
authors.affiliation: Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Oxford University, Oxford, United Kingdom.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Dean
authors.affiliation: Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Tim
authors.initials: T
authors.lastname: Smallie
authors.affiliation: Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Buckley
authors.affiliation: Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom a.r.clark@bham.ac.uk.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Clark
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D054638:Dual Specificity Phosphatase 1 / Q000172:deficiency / Q000378:metabolism; D025461:Feedback, Physiological; D020869:Gene Expression Profiling; D007249:Inflammation / Q000235:genetics / Q000473:pathology*; D018836:Inflammation Mediators / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology*; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics*; D014158:Transcription, Genetic; D051816:Tristetraprolin / Q000235:genetics*
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D051816:Tristetraprolin; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse
keywords: dual-specificity phosphatase 1; inflammation; macrophages; posttranscriptional RNA-binding proteins; tristetraprolin