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J. Biol. Chem., Vol. 283, Issue 18, 12120-12128, May 2, 2008

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Transcriptional Regulation of EGR-1 by the Interleukin-1-JNK-MKK7-c-Jun Pathway^*

Elke Hoffmann¹, Judith Ashouri¹, Sabine Wolter¹, Anneke Doerrie, Oliver Dittrich-Breiholz, Heike Schneider, Erwin F. Wagner, Jakob Troppmair^¶, Nigel Mackman^||, and Michael Kracht^2**

From the Institute of Pharmacology, Medical School Hannover, D-30625 Hannover, Germany, Institute of Molecular Pathology, Vienna, A-1030, Austria, ^¶Daniel-Swarovski-Research Laboratory, Department of General and Transplant Surgery, Innsbruck Medical University, 6020 Innsbruck, Austria, ^||The Scripps Research Institute, La Jolla, Califorina 92037, and ^**Rudolf-Buchheim-Institute of Pharmacology, Justus-Liebig-University Giessen, D-35392 Giessen, Germany

The proinflammatory cytokine interleukin (IL)-1 activates several hundred genes within the same cell. This occurs in part by activation of the MKK7-JNK-c-Jun signaling pathway whose precise role in the regulation of individual inflammatory genes is still incompletely understood. To identify the genes that are under specific control of activated JNK, we used a JNK-MKK7 fusion protein. Genome-wide microarray analysis revealed EGR-1 as the transcript that was most strongly induced by JNK-MKK7. IL-1-stimulated EGR-1 mRNA and protein expression were impaired in cells lacking JNK or c-Jun. Transcriptional activation of the EGR-1 promoter by JNK-MKK7 or by IL-1 required a single upstream AP-1 site and three distal serum-response elements (SRE). Reconstitution experiments in c-Jun-deficient cells revealed that c-Jun is required for EGR-1 transcription through both the AP-1 site and the distal SREs. By chromatin immunoprecipitation analysis, we found IL-1-inducible recruitment of c-Jun to the AP-1 site and to the region containing the three distal SREs. These experiments suggest that c-Jun plays a dual role in EGR-1 transcription. It directly binds to the AP-1 element, and at the same time it is essential for promoter activation through the three distal SREs by an indirect unknown mechanism. As predicted by TRANSFAC analysis and verified by ChIP experiments, IL-1-induced EGR-1 protein binds to the promoter regions of inflammatory mediators such as IL-6, IL-8, and CCL2. Furthermore, short interfering RNA-mediated suppression of EGR-1 partially suppresses IL-1-inducible transcription of IL-8, IL-6, and CCL2. In summary, we provide novel evidence for a complex c-Jun-mediated mechanism that is essential for inducible EGR-1 expression. We identify this pathway as a previously unrecognized part of a multistep gene regulatory network that controls cytokine and chemokine expression via the IL-1-MKK7-JNK-c-Jun-EGR-1 pathway.

Received for publication, January 23, 2008 , and in revised form, February 8, 2008.

^* This work was supported by grants from the Deutsche Forschungsgemeinschaft Kr1143/5-1, Kr1143/6-1, SFB566/B06, and SFB566/Z02 (to M. K.) and the University of California, San Francisco School of Medicine Pathways of Discovery Research Fellowship (to J. A.). 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 These authors contributed equally to this work.

² To whom correspondence should be addressed: Rudolf-Buchheim-Institute of Pharmacology, Justus-Liebig-University Giessen, Frankfurter Strasse 107, D-35392 Giessen, Germany. Tel.: 49-0641-99-47600; Tel./Fax: 49-0641-99-47619; E-mail: Michael.Kracht{at}pharma.med.uni-giessen.de.

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