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Induces the Human IL-10 Gene by Recruiting Both IFN Regulatory Factor 1 and Stat31
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* Institute for Immunology, University of Munich, Munich, Germany;
Division of Immunology, University of Leicester, Leicester, United Kingdom;
Institute of Mammalian Genetics, GSF National Research Center for Environment and Health, Neuherberg and Genomatix Software, Munich, Germany; and
Clinical Cooperation Group Aerosols in Medicine, GSF National Research Center for Environment and Health, Institute for Inhalation Biology and Asklepios Hospitals, Gauting, Germany
The anti-inflammatory cytokine IL-10 can be induced by type I IFNs, but the molecular mechanisms involved have remained elusive. With in silico analysis of the human IL-10 promoter we identified a module consisting of an IFN regulatory factor 1 (IRF-1) site and a Stat3 site. We demonstrate that IFN-
will induce the binding of IRF-1 and Stat3 to the respective motifs. Mutational analysis revealed that inactivation of the IRF-1 motif substantially reduces trans-activation from 5- to 2-fold and that inactivation of the Stat3 motif completely ablates trans-activation by IFN-. The dominant role of Stat3 in this module was confirmed with the blockade of trans-activation by a dominant negative Stat3. By contrast, Stat1 contributes a minor proportion to the DNA binding to the Stat site, and overexpression will counteract Stat3-mediated trans-activation. The data show that IFN- induces the IL-10 gene via a module consisting of interdependent IRF-1 and Stat3 motifs. Of note, LPS-induced trans-activation does not target this module, since it is independent of the IRF-1 motif but completely depends on Stat3.
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