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* 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 and
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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This study was supported by Austrian Science Fund (Fonds zur Förderungder Wissenschaftlichen Forschung) Grants SFB F28 and P16726-B14, European Science Foundation Grant I27-B03 (to P.K.), Austrian Science Fund Fonds zur Förderungder Wissenschaftlichen Forschung Grant SFB F28 and the Austrian Federal Ministry for Science and Research Grant Bundesministerium für Wissenschaft und Forschung GZ200.112/1-VI/1/2004 (to M.M.), National Institutes of Health Grant AI062921 (to P.J.M.), and Deutsche Forschungsgemeinschaft Grants Sonderforschungsbereich 576/TP-A11 and LA1262/4-1 (to R.L.).
2 B.S. and F.K. contributed equally to this work.
3 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
4 Abbreviations used in this paper: UTR, untranslated region; ARE, AU-rich element; DUSP1, dual-specificity phosphate 1; BMDM, bone marrow-derived macrophage; TTP, tristetraprolin; WT, wild type; qRT-PCR, quantitative RT-PCR; fwd, forward; rev, reverse; SOCS, suppressor of cytokine signaling; SB, SB203580.
5 The online version of this article contains supplemental material.
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