Gain-of-function mutation of tristetraprolin impairs negative feedback control of macrophages in vitro, yet has overwhelmingly anti-inflammatory consequences in vivo.

The mRNA destabilizing factor tristetraprolin (TTP) binds in a sequence-specific manner to the 3' untranslated regions of many pro-inflammatory mRNAs and recruits complexes of nucleases to promote rapid mRNA turnover. Mice lacking TTP develop a severe, spontaneous inflammatory syndrome characterized by over-expression 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. Perturbation of TTP function may therefore have mixed effects on inflammatory responses, either increasing or decreasing the expression of pro-inflammatory factors via direct or indirect mechanisms. We recently described a knock-in mouse strain in which the substitution of two amino acids of 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 decreased expression of IL-10.