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Tristetraprolin Is Required for Full Anti-Inflammatory Response of Murine Macrophages to IL-10

Barbara Schaljo^*, Franz Kratochvill^*, Nina Gratz^*, Iwona Sadzak^*, Ines Sauer^*, Michael Hammer^||, Claus Vogl, Birgit Strobl^,, Mathias Müller^,, Perry J. Blackshear, Valeria Poli^¶, Roland Lang^||, Peter J. Murray^** and Pavel Kovarik^*

^*Max F. Perutz Laboratories, Department of Microbiology and Immunobiology, University of Vienna, Vienna, Austria; Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna; University Center Biomodels Austria GmbH, University of Veterinary Medicine Vienna, Vienna, Austria; Laboratory of Neurobiology, National Institute of Environmental Health Science, Research Triangle Park, NC 27709; ^¶Department of Genetics, Biology and Biochemistry, Molecular Biology Center, University of Turin, Turin, Italy; ^||Institute of Medical Microbiology, Immunology and Hygiene, Technical University Munich, Munich, Germany; ^#Institute of Microbiology, Immunology and Hygiene, University Hospital Erlangen, Erlangen, Germany; and ^**Departments of Infectious Diseases and Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38105

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-, a potent proinflammatory mediator that is the target for multiple anti-TNF- 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- and IL-1 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.

Address correspondence and reprint requests to Dr. Pavel Kovarik, Max F. Perutz Laboratories, Department of Microbiology and Immunobiology, University of Vienna, Dr. Bohr-Gasse 9, A-1030 Vienna, Austria. E-mail address: pavel.kovarik{at}univie.ac.at