Gain-of-Function Mutation of Tristetraprolin Impairs Negative Feedback Control of Macrophages In Vitro yet Has Overwhelmingly Anti-Inflammatory Consequences In 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 function in vitro. However, the in vivo effects of TTP mutation are uniformly anti-inflammatory despite the decreased expression of IL-10.

KEYWORDS:

• dual-specificity phosphatase 1
• inflammation
• macrophages
• posttranscriptional RNA-binding proteins
• tristetraprolin

Supplemental material for this article may be found at https://doi.org/10.1128/MCB.00536-16.

ACKNOWLEDGMENTS

This work was supported by program grant 19614 from Arthritis Research UK. We are grateful to Fiona Powrie and Claire Pearson (Oxford) for provision of Il10^−/− bone marrow.

We have no conflicts of interest with regard to the subjects of this paper.

J.D.O., E.A.R., T.S., Q.D., T.T., and D.M. performed experiments. M.L.R. analyzed microarray data. D.R.S. and T.C. interpreted data. J.L.D., C.D.B., and A.R.C. devised and interpreted experiments. A.R.C. wrote the manuscript, with input from all coauthors.