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J. Biol. Chem., Vol. 281, Issue 47, 36173-36179, November 24, 2006

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Legionella pneumophila Induces IFN in Lung Epithelial Cells via IPS-1 and IRF3, Which Also Control Bacterial Replication^*

Bastian Opitz¹², Maya Vinzing¹, Vincent van Laak, Bernd Schmeck, Guido Heine, Stefan Günther^¶, Robert Preissner^¶, Hortense Slevogt, Philippe Dje N'Guessan, Julia Eitel, Torsten Goldmann^||, Antje Flieger^**, Norbert Suttorp, and Stefan Hippenstiel

From the Department of Internal Medicine/Infectious Diseases and Pulmonary Medicine, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany, the Department of Dermatology and Allergy, Allergy Center Charité, Charité Universitätsmedizin Berlin, Schumannstrasse 20/21, 10117 Berlin, Germany, ^¶Institute of Biochemistry Charité, Monbijoustrasse 2, 10117 Berlin, Germany, ^||Clinical and Experimental Pathology, Research Center Borstel, Parkallee 3, 23845 Borstel, Germany, and ^**Robert Koch Institute, Research Group NG5 Pathogenesis of Legionella Infections, Nordufer 20, D-13353 Berlin, Germany

Legionella pneumophila, a Gram-negative facultative intracellular bacterium, causes severe pneumonia (Legionnaires' disease). Type I interferons (IFNs) were so far associated with antiviral immunity, but recent studies also indicated a role of these cytokines in immune responses against (intracellular) bacteria. Here we show that wild-type L. pneumophila and flagellin-deficient Legionella, but not L. pneumophila lacking a functional type IV secretion system Dot/Icm, or heat-inactivated Legionella induced IFN expression in human lung epithelial cells. We found that factor (IRF)-3 and NF-B-p65 translocated into the nucleus and bound to the IFN gene enhancer after L. pneumophila infection of lung epithelial cells. RNA interference demonstrated that in addition to IRF3, the caspase recruitment domain (CARD)-containing adapter molecule IPS-1 (interferon- promoter stimulator 1) is crucial for L. pneumophila-induced IFN expression, whereas other CARD-possessing molecules, such as RIG-I (retinoic acid-inducible protein I), MDA5 (melanoma differentiation-associated gene 5), Nod27 (nucleotide-binding oligomerization domain protein 27), and ASC (apoptosis-associated speck-like protein containing a CARD) seemed not to be involved. Finally, bacterial multiplication assays in small interfering RNA-treated cells indicated that IPS-1, IRF3, and IFN were essential for the control of intracellular replication of L. pneumophila in lung epithelial cells. In conclusion, we demonstrated a critical role of IPS-1, IRF3, and IFN in Legionella infection of lung epithelium.

Received for publication, May 15, 2006 , and in revised form, August 7, 2006.

^* This work was supported in part by grants from the Bundesministerium für Bildung und Forschung, BMBF Competence Network CAPNETZ C15 (to S. H.), CAPNETZ C15 (to B. S.), and CAPNETZ C4 (to N. S.). Parts of this work will be included in the M.D. thesis of M. V. 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 two authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Internal Medicine/Infectious Diseases and Respiratory Medicine, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. Tel.: 49-30-450-553383; Fax: 49-30-450-553992; E-mail: bastian.opitz{at}charite.de.

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