Tristetraprolin regulation of interleukin-22 production

Abstract

Interleukin (IL)-22 is a STAT3-activating cytokine displaying characteristic AU-rich elements (ARE) in the 3′-untranslated region (3′-UTR) of its mRNA. This architecture suggests gene regulation by modulation of mRNA stability. Since related cytokines undergo post-transcriptional regulation by ARE-binding tristetraprolin (TTP), the role of this destabilizing protein in IL-22 production was investigated. Herein, we demonstrate that TTP-deficient mice display augmented serum IL-22. Likewise, IL-22 mRNA was enhanced in TTP-deficient splenocytes and isolated primary T cells. A pivotal role for TTP is underscored by an extended IL-22 mRNA half-life detectable in TTP-deficient T cells. Luciferase-reporter assays performed in human Jurkat T cells proved the destabilizing potential of the human IL-22-3′-UTR. Furthermore, overexpression of TTP in HEK293 cells substantially decreased luciferase activity directed by the IL-22-3′-UTR. Transcript destabilization by TTP was nullified upon cellular activation by TPA/A23187, an effect dependent on MEK1/2 activity. Accordingly, IL-22 mRNA half-life as determined in TPA/A23187-stimulated Jurkat T cells decreased under the influence of the MEK1/2 inhibitor U0126. Altogether, data indicate that TTP directly controls IL-22 production, a process counteracted by MEK1/2. The TTP-dependent regulatory pathway described herein likely contributes to the role of IL-22 in inflammation and cancer and may evolve as novel target for pharmacological IL-22 modulation.

Oncogenic RAS Signaling Promotes Tumor Immunoresistance by Stabilizing PD-L1 mRNA

“…ERK has been shown to phosphorylate ( Taylor et al., 1995 ) and negatively regulate TTP activity and expression ( Bourcier et al., 2011 , Deleault et al., 2008 , Essafi-Benkhadir et al., 2007 , Härdle et al., 2015 ). Inhibition of MEK decreased phosphorylation of TTP at PXSP (ERK target-site consensus) and RXXS/T (RSK/AKT target-site consensus) motifs ( Figures 4 D and 4E), confirming that TTP is regulated by phosphorylation downstream of MEK signaling in cancer cells.…”

Effect of the p53–tristetraprolin–stathmin-1 pathway on trophoblasts at maternal–fetal interface

“…A well-characterized example is TNF-α, whose expression is efficiently controlled by TTP as a part of a negative feedback loop [ 32 ]. TTP modulates various other inflammatory mediators, such as macrophage inflammatory protein-2 (MIP-2) [ 33 ], GM-CSF [ 34 ], interferon-γ [ 35 ], IL-22 [ 36 ], IL-10 [ 37 ], IL-6 [ 38 ], and post-transcriptional gene regulation is frequently organized in functional units. TTP is believed to play a key role in tumorigenesis, as its mRNA encodes the LATS2 tumor suppressor and the E6-AP ligase that directs p53 destruction [ 39 ].…”

The RNA-binding protein tristetraprolin regulates RALDH2 expression by intestinal dendritic cells and controls local Treg homeostasis

“…32 As TTP directly controls IL-22 production, this could also promote local mucosal integrity and homeostasis. 33 d Pregnant Zfp36 fl/fl or Zfp36 ΔDC mice were fed with a vitamin A-deficient diet (VAD) that was maintained in the pups after weaning until sacrifice at 8 weeks of age, followed by flow cytometry experiments (e, f). Control mice were fed with a normal diet.…”