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The p38 MAPK pathway inhibits tristetraprolin-directed decay of interleukin-10 and pro-inflammatory mediator mRNAs in murine macrophages.

ABSTRACT: 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.

SUBMITTER: Tudor C

PROVIDER: S-EPMC4798241 | biostudies-literature | 2009 Jun

REPOSITORIES: biostudies-literature

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The p38 MAPK pathway inhibits tristetraprolin-directed decay of interleukin-10 and pro-inflammatory mediator mRNAs in murine macrophages.

Tudor Corina C Marchese Francesco P FP Hitti Edward E Aubareda Anna A Rawlinson Lesley L Gaestel Matthias M Blackshear Perry J PJ Clark Andrew R AR Saklatvala Jeremy J Dean Jonathan L E JL

FEBS letters 20090503 12

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 t ...[more]

PMID: 19416727

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Project description:The activation of monocytes and macrophages is associated with steroid-resistant (SR) asthma. Interleukin-35 (IL-35) is an important anti-inflammatory cytokine, but its regulatory effects on monocytes in patients with SR asthma is not fully understood. Based on clinical response to oral prednisolone, 34 patients with steroid-sensitive (SS) asthma and 20 patients with SR asthma were enrolled in the present study. Serum IL-35 levels were analyzed using the Luminex 200 platform. Monocytes from patients with asthma were pretreated with IL-35 followed by dexamethasone (DEX) and lipopolysaccharide (LPS), then corticosteroid sensitivity was evaluated according to the half-maximal inhibitory concentration of DEX with respect to LPS-induced IL-6 maximal production in monocytes (DEX-IC50). The percentage of maximal inhibition of IL-6 by DEX was presented as Emax. Phosphorylated-P38 mitogen activated kinase (p-p38 MAPK) and mitogen-activated protein kinase phosphatase-1 (MKP-1) were examined by flow cytometry and reverse transcription-quantitative PCR analysis, respectively. Glucocorticoid receptor (GR) binding to the glucocorticoid response element (GRE) was assessed by chromatin immunoprecipitation. Compared with patients with SS asthma, patients with SR asthma had lower IL-35 expression levels (P<0.05). Correlation analysis results demonstrated that the expression levels of IL-35 showed a weak negative correlation with log DEX-IC50 (r=-0.351; P<0.01) and a moderate positive correlation with Emax value (r=0.4501; P<0.01) in all patients with asthma. Moreover, IL-35 enhanced DEX-suppressed IL-6 production and the DEX-induced upregulation of the MKP-1 mRNA expression level in monocytes from both patient groups (P<0.01). In addition, IL-35 inhibited p-p38 MAPK expression in monocytes, and these effects were mediated via an increase in DEX-induced GR binding to GRE. Therefore, IL-35 may be involved in the corticosteroid enhancing effects in monocytes of patients with SR and SS asthma, suggesting potential benefits of IL-35 supplementation in asthmatics with DEX.

Dataset Information

The p38 MAPK pathway inhibits tristetraprolin-directed decay of interleukin-10 and pro-inflammatory mediator mRNAs in murine macrophages.

Publications

The p38 MAPK pathway inhibits tristetraprolin-directed decay of interleukin-10 and pro-inflammatory mediator mRNAs in murine macrophages.

Similar Datasets

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