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J. Biol. Chem., Vol. 279, Issue 51, 53241-53247, December 17, 2004

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Streptococcus pneumoniae-induced p38 MAPK-dependent Phosphorylation of RelA at the Interleukin-8 Promotor^*

Bernd Schmeck, Janine Zahlten, Kerstin Moog, Vincent van Laak, Sylvia Huber, Andreas C. Hocke, Bastian Opitz, Elke Hoffmann¶, Michael Kracht¶, Jens Zerrahn||, Sven Hammerschmidt**, Simone Rosseau, Norbert Suttorp, and Stefan Hippenstiel

From the Department of Internal Medicine/Infectious Diseases, Charité, University Medicine Berlin, 13353 Berlin, the ^¶Institute of Pharmacology, Medizinische Hochschule Hannover, 30623 Hannover, the ^||Max-Planck-Institute of Infection Biology, 10117 Berlin, and the ^**Research Center for Infectious Diseases, University of Würzburg, 97070 Würzburg, Germany

Streptococcus pneumoniae is the major cause of community-acquired pneumonia and one of the most common causes of death by infectious disease in industrialized countries. Little is known concerning the mechanisms of target cell activation in this disease. The present study shows that NF-B and p38 MAPK signaling pathways contribute to chemokine synthesis by lung epithelial cells in response to pneumococci. In infected lungs of mice pneumococci stimulate expression of the interleukin (IL)-8 homolog keratinocyte-derived chemokine and granulocyte-macrophage colony-stimulating factor, as well as activate p38 MAPK. Human bronchial epithelium was chosen as a cellular model, because it establishes the first barrier against pathogens, and little is known about its function in innate immunity. Pneumococci infection induces expression of IL-8 and granulocyte-macrophage colony-stimulating factor as well as activation of p38 MAPK in human bronchial epithelial cells (BEAS-2B). Inhibition of p38 MAPK activity by SB202190 and SB203580 blocks pneumococci-induced cytokine release. In mouse lungs in vivo as well as in cultured cells, pneumococci activate NF-BinanIB kinase-dependent manner. Inhibition of p38 MAPK by chemical inhibitors or by RNA interference targeting p38 reduces pneumococci-induced NF-B-dependent gene transcription. Blockade of p38 activity did not affect inducible nuclear translocation and recruitment of NF-B/RelA to the IL-8 promotor but did reduce the level of phosphorylated RelA (serine 536) at IL-8 promotor and inhibited pneumococci-mediated recruitment of RNA polymerase II to IL-8 promotor. Thus, p38 MAPK contributes to pneumococci-induced chemokine transcription by modulating p65 NF-B-mediated transactivation.

Received for publication, December 15, 2003 , and in revised form, October 12, 2004.

^* This work was supported in part by Bundesministerium für Bildung und Forschung Grants CAPNETZ C15 (to B. S.), CAPNETZ C15 and BMBF-NBL3 (to S. Hippenstiel), CAPNETZ C8 (to S. Hammerschmidt), CAPNETZ C4 (to N. S.), and CAPNETZ C4 (to S. R.) and by Deutsche Forschungsgemeinschaft Grants Kr1143/4-1 (to M. K.) and GRK325 (to J. Z.). 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.

Submitted in partial fulfillment of the requirements for a Ph.D. at University Medicine Berlin.

To whom correspondence should be addressee: Dept. of Internal Medicine/Infectious Diseases, Charité, University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. Tel.: 49-30-450-553052; Fax: 49-30-450-553906; E-mail: stefan.hippenstiel{at}charite.de.

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