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.

Download full-text


Available from: Matthias Gaestel
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Birch bark has a long lasting history as a traditional medicinal remedy to accelerate wound healing. Recently, the efficacy of birch bark preparations has also been proven clinically. As active principle pentacyclic triterpenes are generally accepted. Here, we report a comprehensive study on the underlying molecular mechanisms of the wound healing properties of a well-defined birch bark preparation named as TE (triterpene extract) as well as the isolated single triterpenes in human primary keratinocytes and porcine ex-vivo wound healing models. We show positive wound healing effects of TE and betulin in scratch assay experiments with primary human keratinocytes and in a porcine ex-vivo wound healing model (WHM). Mechanistical studies elucidate that TE and betulin transiently upregulate pro-inflammatory cytokines, chemokines and cyclooxygenase-2 on gene and protein level. For COX-2 and IL-6 this increase of mRNA is due to an mRNA stabilizing effect of TE and betulin, a process in which p38 MAPK and HuR are involved. TE promotes keratinocyte migration, putatively by increasing the formation of actin filopodia, lamellipodia and stress fibers. Detailed analyses show that the TE components betulin, lupeol and erythrodiol exert this effect even in nanomolar concentrations. Targeting the actin cytoskeleton is dependent on the activation of Rho GTPases. Our results provide insights to understand the molecular mechanism of the clinically proven wound healing effect of birch bark. TE and betulin address the inflammatory phase of wound healing by transient up-regulation of several pro-inflammatory mediators. Further, they enhance migration of keratinocytes, which is essential in the second phase of wound healing. Our results, together with the clinically proven efficacy, identify birch bark as the first medical plant with a high potential to improve wound healing, a field which urgently needs effective remedies.
    Full-text · Article · Jan 2014 · PLoS ONE
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Tristetraprolin (TTP) is a key mediator of processes such as inflammation resolution, the inhibition of autoimmunity and in cancer. It carries out this role by the binding and degradation of mRNA transcripts, thereby decreasing their half-life. Transcripts modulated by TTP encode proteins such as cytokines, pro-inflammatory agents and immediate-early response proteins. TTP can also modulate neoplastic phenotypes in many cancers. TTP is induced and functionally regulated by a spectrum of both pro- and anti-inflammatory cytokines, mitogens and drugs in a MAPK-dependent manner. So far the contribution of p38 MAPK to the regulation of TTP expression and function has been best described. Our results demonstrate the induction of the gene coding TTP (ZFP36) by EGF through the ERK1/2-dependent pathway and implicates the transcription factor ELK-1 in this process. We show that ELK-1 regulates ZFP36 expression by two mechanisms: by binding the ZFP36 promoter directly through ETS-binding site (+ 883 to +905 bp) and by inducing expression of EGR-1, which in turn increases ZFP36 expression through sequences located between -111 and -103 bp. EGF activates TTP expression via ELK-1 and EGR-1 transcription factors.
    Full-text · Article · Mar 2012 · BMC Molecular Biology
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Since its recent discovery, interleukin-23 has been shown to be involved in the pathogenesis of autoimmune diseases favoring the development of a T cell subset referred to as T helper 17. Glucocorticoids are widely employed in inflammatory and autoimmune diseases as they inhibit pro-inflammatory signaling and prevent production of inflammation mediators. Very limited information is available about the efficacy of synthetic glucocorticoids in containing the expression of interleukin-23 under cell activation. We demonstrate here that the glucocorticoid analogue dexamethasone administered to human monocyte-derived macrophages is indeed able to restrain the expression of interleukin-23 once it has been triggered by a pro-inflammatory stimulus. This effect of dexamethasone is here demonstrated being secondary to suppression of p38 MAPK activity, and involving a protein phosphatase--likely MAPK phosphatase-1 (MKP-1). Results reported in this paper show that a 10 nanomolar dose of dexamethasone not only prevents inflammatory activation but is also efficacious in confining active inflammation. This effect is here demonstrated not to occur through "canonical" inhibition of the NF-κB transcription factor but through a distinct cascade of down-modulation, that underlines the importance of the transactivating activity of glucocorticoid receptor in the context of its anti-inflammatory action.
    Full-text · Article · Jul 2011 · BMC Pharmacology
Show more