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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




Journal article


Mol Cell Biol

Publication Date





dual-specificity phosphatase 1, inflammation, macrophages, posttranscriptional RNA-binding proteins, tristetraprolin, Animals, Bone Marrow Cells, Cytokines, Dual Specificity Phosphatase 1, Feedback, Physiological, Gene Expression Profiling, Inflammation, Inflammation Mediators, Macrophages, Mice, Inbred C57BL, Mutation, Transcription, Genetic, Tristetraprolin