Bi-phased regulation of the post-transcriptional inflammatory response by Tristetraprolin levels

Abstract

AU-rich elements (AREs) are cis-acting instability and translation inhibition elements that are present in the 3ʹUTR of most inducible inflammatory mRNAs such as TNF and Cxcl2. mRNAs that contain AREs are, by default, repressed and only transiently expressed in response to stimuli. They are targeted by the inducible RNA-binding protein Tristetraprolin (TTP) which blocks their translation and facilitates their decay, thereby contributing to the quick termination of their expression. The exogenous over-expression of TTP in HEK293 cells can unexpectedly lead to the upregulation and extended expression of a nanoLuciferase reporter that contains the ARE of TNF. Here we show that, a moderate downregulation of the highly expressed endogenous TTP after LPS induction by siRNA in macrophages can lead to a reduction in the release of TNF and Cxcl2. We propose that, in contrast to their canonical function, very high levels of induced TTP at the onset of the inflammatory response can enhance the expression of ARE-mRNAs at the post-transcriptional level, independently of phosphorylation status. As the inflammatory response progresses, TTP levels diminish but they continuously regain their ability to reduce the expression of ARE-mRNAs to reach a turning point of ‘optimal TTP level’ with a maximum ability to repress ARE-mRNA expression. Below this level, a further reduction in TTP levels now leads to the loss of canonical-TTP function resulting in increased ARE-mRNA expression. These novel findings should contribute to the understanding of feedback loops that control the kinetics of the inflammatory response.