Tudor C, Marchese FP, Hitti E, Aubareda A, Rawlinson L, Gaestel M et al.. The p38 MAPK pathway inhibits tristetraprolin-directed decay of interleukin-10 and pro-inflammatory mediator mRNAs in murine macrophages. FEBS Lett 583: 1933-1938

Kennedy Institute of Rheumatology Division, Imperial College London, London, United Kingdom.
FEBS letters (Impact Factor: 3.17). 06/2009; 583(12):1933-8. DOI: 10.1016/j.febslet.2009.04.039
Source: PubMed


p38 mitogen-activated protein kinase (MAPK) stabilises pro-inflammatory mediator mRNAs by inhibiting AU-rich element (ARE)-mediated decay. We show that in bone-marrow derived murine macrophages tristetraprolin (TTP) is necessary for the p38 MAPK-sensitive decay of several pro-inflammatory mRNAs, including cyclooxygenase-2 and the novel targets interleukin (IL)-6, and IL-1alpha. TTP(-/-) macrophages also strongly overexpress IL-10, an anti-inflammatory cytokine that constrains the production of the IL-6 despite its disregulation at the post-transcriptional level. TTP directly controls IL-10 mRNA stability, which is increased and insensitive to inhibition of p38 MAPK in TTP(-/-) macrophages. Furthermore, TTP enhances deadenylation of an IL-10 3'-untranslated region RNA in vitro.

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    • "p38 MAPK functions by activating or inhibiting mRNA stability or destability factors like HuR and TTP [61], [62]. HuR exerts its stabilizing function only when localized in the cytosol [63]. "
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    • "The activity of TTP is regulated predominantly via its phosphorylation by MAP kinases (in particular p38 and ERK1/2), kinases downstream of MAPKs (including MK2, the p38 substrate or MK3) or AKT in response to pro-inflammatory cytokines (TNFα, IL-1β, IFNγ), LPS and anti-inflammatory factors (TGFβ, dexamethasone). The TTP protein sequence contains several key serine/threonine residues, the modification of which was previously shown to determine the ability of TTP to recruit the mRNA-degradation machinery, bind transcripts, be shuttled to P-bodies or stress granules and its nuclear/cytoplasmic localization and protein stability [7-12]. "
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    • "For example, MSK1 (mitogen- and stress-activated kinase 1), a downstream target of p38 MAPK, phosphorylates serine 276 of p65 enhancing transcription [36]. In addition, p38 favors inflammation also by post-transcriptional stabilization of pro-inflammatory mRNAs that contain adenylate/uridylate-rich elements in the 3' untranslated region [47-49]. "
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