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J. Biol. Chem., Vol. 281, Issue 39, 28822-28830, September 29, 2006

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N-(3-Oxo-acyl)homoserine Lactones Signal Cell Activation through a Mechanism distinct from the Canonical Pathogen-associated Molecular Pattern Recognition Receptor Pathways^*

Vladimir V. Kravchenko¹, Gunnar F. Kaufmann^¶1, John C. Mathison, David A. Scott, Alexander Z. Katz, Malcolm R. Wood^||, Andrew P. Brogan^¶, Mandy Lehmann, Jenny M. Mee^¶, Kazunori Iwata, Qilin Pan, Colleen Fearns, Ulla G. Knaus, Michael M. Meijler^¶, Kim D. Janda^¶**2, and Richard J. Ulevitch³

From the Departments of Immunology and Chemistry and the ^||Core Microscopy Facility, The Scripps Research Institute, ^¶The Skaggs Institute for Chemical Biology, and ^**Worm Institute of Research and Medicine, La Jolla, California 92037

Innate immune system receptors function as sensors of infection and trigger the immune responses through ligand-specific signaling pathways. These ligands are pathogen-associated products, such as components of bacterial walls and viral nuclear acids. A common response to such ligands is the activation of mitogen-activated protein kinase p38, whereas double-stranded viral RNA additionally induces the phosphorylation of eukaryotic translation initiation factor 2 (eIF2). Here we have shown that p38 and eIF2 phosphorylation represent two biochemical markers of the effects induced by N-(3-oxo-acyl)homoserine lactones, the secreted products of a number of Gram-negative bacteria, including the human opportunistic pathogen Pseudomonas aeruginosa. Furthermore, N-(3-oxo-dodecanoyl)homoserine lactone induced distension of mitochondria and the endoplasmic reticulum as well as c-jun gene transcription. These effects occurred in a wide variety of cell types including alveolar macrophages and bronchial epithelial cells, requiring the structural integrity of the lactone ring motif and its natural stereochemistry. These findings suggest that N-(3-oxo-acyl)homoserine lactones might be recognized by receptors of the innate immune system. However, we provide evidence that N-(3-oxo-dodecanoyl)homoserine lactone-mediated signaling does not require the presence of the canonical innate immune system receptors, Toll-like receptors, or two members of the NLR/Nod/Caterpillar family, Nod1 and Nod2. These data offer a new understanding of the effects of N-(3-oxo-dodecanoyl)homoserine lactone on host cells and its role in persistent airway infections caused by P. aeruginosa.

Received for publication, July 12, 2006 , and in revised form, August 4, 2006.

^* This work was supported by Grants 5P01GM037696 (to R. J. U.) and AI055781 (to K. D. J.) from the National Institutes of Health and by a grant from the Skaggs Institute for Chemical Biology (to K. D. J.). 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 may be addressed: Dept. of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla, CA 92037. Tel.: 858-784-2516; Fax: 858-784-2595; E-mail: kdjanda{at}scripps.edu. ³To whom correspondence may be addressed: Dept. of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla, CA 92037. Tel.: 858-784-8219; Fax: 858-784-8333; E-mail: ulevitch{at}scripps.edu.

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