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J. Biol. Chem., Vol. 283, Issue 45, 30513-30521, November 7, 2008

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Aspergillus fumigatus-induced Interleukin-8 Synthesis by Respiratory Epithelial Cells Is Controlled by the Phosphatidylinositol 3-Kinase, p38 MAPK, and ERK1/2 Pathways and Not by the Toll-like Receptor-MyD88 Pathway^*

Viviane Balloy, Jean-Michel Sallenave, Yongzheng Wu, Lhousseine Touqui, Jean-Paul Latgé^¶, Mustapha Si-Tahar, and Michel Chignard¹

From the Unité de Défense Innée et Inflammation and ^¶Unité des Aspergillus, Institut Pasteur, Paris 75015, France and Inserm, U874, Paris 75015, France

Previous studies have established that phagocytes are key cells of the pulmonary innate immune defense against A. fumigatus, an opportunistic fungus responsible of invasive pulmonary aspergillosis. Macrophages detect A. fumigatus via Toll-like receptors 2 and 4 (TLR2 and -4) and respond by the MyD88-NF-B-dependent synthesis of inflammatory mediators. In the present study, we demonstrate that respiratory epithelial cells also sense A. fumigatus and participate in the host defense. Thus, the interaction of respiratory epithelial cells with germinating but not resting conidia of A. fumigatus results in interleukin (IL)-8 synthesis that is controlled by phosphatidylinositol 3-kinase, p38 MAPK, and ERK1/2. Using MyD88-dominant negative transfected cells, we also show that IL-8 production is not dependent on the TLR-MyD88 pathway, although the MyD88 pathway is activated by A. fumigatus and leads to NF-B activation. Thus, our results provide evidence for the existence of two independent signaling pathways activated in respiratory epithelial cells by A. fumigatus, one that is MyD88-dependent and another that is My88-independent and involved in IL-8 synthesis.

Received for publication, April 24, 2008 , and in revised form, July 29, 2008.

^* This work was supported by the nonprofit association Vaincre la Mucoviscidose. 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 To whom correspondence should be addressed: Défense Innée et Inflammation, Inserm U874, Institut Pasteur, 25 Rue du Dr. Roux, 75015 Paris, France. Tel.: 33-1-45-68-86-88; Fax: 33-1-45-68-87-03; E-mail: chignard{at}pasteur.fr.

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