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| The EMBO Journal
(2001) 20, 3760–3770, doi:10.1093/emboj/20.14.3760 |
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| Interleukin-10 targets p38 MAPK to modulate ARE-dependent TNF mRNA translation and limit intestinal pathology |
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| Dimitris Kontoyiannis1, Alexey Kotlyarov2, Ester Carballo3, Lena Alexopoulou1, 4, Perry J. Blackshear3, Matthias Gaestel2, Roger Davis5, Richard Flavell4 and George Kollias1 |
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1 Institute of Immunology, BSRC 'Alexander Fleming', 166 72 Vari, Greece 2 Innovationskolleg Zellspezialisierung, Martin-Luther-Universität Halle Wittenberg, D-06120 Halle, Germany 3 Laboratory of Signal Transduction, NIEHS, National Institutes of Health, Research Triangle Park, NC 27709, USA 4 Section of Immunobiology and Howard Hughes Medical Institute, Yale University School of Medicine, 310 Cedar Street, New Haven, CT 06520-8011, USA 5 Howard Hughes Medical Institute, Program in Molecular Medicine, Department of Biochemistry and Molecular Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA To whom correspondence should be addressed George Kollias, giorgos_kollias@hol.gr Received 20 December 2000; Revised 3 May 2001; Accepted 29 May 2001. |
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| Abstract |
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| Interleukin-10 (IL-10) is a key inhibitory signal of inflammatory responses that regulates the production of potentially pathogenic cytokines like tumor necrosis factor (TNF). We show here that the development of chronic intestinal inflammation in IL-10-deficient mice requires the function of TNF, indicating that the IL-10/TNF axis regulates mucosal immunity. We further show that IL-10 targets the 3' AU-rich elements (ARE) of TNF mRNA to inhibit its translation. Moreover, IL-10 does not alter TNF mRNA stability, and its action does not require the presence of the stability-regulating ARE binding factor tristetraprolin, indicating a differential assembly of stability and translation determinants on the TNF ARE. Inhibition of TNF translation by IL-10 is exerted mainly by inhibition of the activating p38/MAPK-activated protein kinase-2 pathway. These results demonstrate a physiologically significant cross-talk between the IL-10 receptor and the stress-activated protein kinase modules targeting TNF mRNA translation. This cross-talk is necessary for optimal TNF production and for the maintenance of immune homeostasis in the gut. |
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| Keywords: animal model, anti-inflammatory, Crohn's disease, gene expression, knockout |
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