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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 function in vitro However, the in vivo effects of TTP mutation are uniformly anti-inflammatory despite the decreased expression of IL-10.

Original publication

DOI

10.1128/mcb.00536-16

Type

Journal article

Journal

Molecular and cellular biology

Publication Date

06/2017

Volume

37

Addresses

Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.

Keywords

Bone Marrow Cells, Macrophages, Animals, Mice, Inbred C57BL, Inflammation, Inflammation Mediators, Cytokines, Gene Expression Profiling, Transcription, Genetic, Mutation, Tristetraprolin, Dual Specificity Phosphatase 1, Feedback, Physiological