Tristetraprolin is Required for Full Anti-inflammatory Response of Murine Macrophages to IL-10

Overview

Journal J Immunol

Specialty Allergy & Immunology

Date 2009 Jun 23

PMID 19542371

Citations 67

Authors

Barbara Schaljo

Franz Kratochvill

Nina Gratz

Iwona Sadzak

Ines Sauer

Michael Hammer

Claus Vogl

Birgit Strobl

Mathias Muller

Perry J Blackshear

Valeria Poli

Roland Lang

Peter J Murray

Pavel Kovarik

Affiliations

Soon will be listed here.

Abstract

IL-10 is essential for inhibiting chronic and acute inflammation by decreasing the amounts of proinflammatory cytokines made by activated macrophages. IL-10 controls proinflammatory cytokine and chemokine production indirectly via the transcription factor Stat3. One of the most physiologically significant IL-10 targets is TNF-alpha, a potent proinflammatory mediator that is the target for multiple anti-TNF-alpha clinical strategies in Crohn's disease and rheumatoid arthritis. The anti-inflammatory effects of IL-10 seem to be mediated by several incompletely understood transcriptional and posttranscriptional mechanisms. In this study, we show that in LPS-activated bone marrow-derived murine macrophages, IL-10 reduces the mRNA and protein levels of TNF-alpha and IL-1alpha in part through the RNA destabilizing factor tristetraprolin (TTP). TTP is known for its central role in destabilizing mRNA molecules containing class II AU-rich elements in 3' untranslated regions. We found that IL-10 initiates a Stat3-dependent increase of TTP expression accompanied by a delayed decrease of p38 MAPK activity. The reduction of p38 MAPK activity releases TTP from the p38 MAPK-mediated inhibition, thereby resulting in diminished mRNA and protein levels of proinflammatory cytokines. These findings establish that TTP is required for full responses of bone marrow-derived murine macrophages to IL-10.

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