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Infection and Immunity, October 2003, p. 5785-5793, Vol. 71, No. 10
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.10.5785-5793.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

The Pseudomonas aeruginosa Autoinducer N-3-Oxododecanoyl Homoserine Lactone Accelerates Apoptosis in Macrophages and Neutrophils

Kazuhiro Tateda,1* Yoshikazu Ishii,1 Manabu Horikawa,2 Tetsuya Matsumoto,1 Shinichi Miyairi,3 Jean Claude Pechere,4 Theodore J. Standiford,5 Masaji Ishiguro,2 and Keizo Yamaguchi1

Department of Microbiology, Toho University School of Medicine, Tokyo,1 Suntory Institute for Bioorganic Research, Osaka,2 Laboratory of Bio-Organic Chemistry, College of Pharmacy, Nihon University, Chiba, Japan,3 Department of Microbiology and Genetics, University of Geneva, Geneva, Switzerland,4 Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109-03605

Received 23 April 2003/ Returned for modification 4 June 2003/ Accepted 16 July 2003

Quorum-sensing systems are critical regulators of the expression of virulence factors of various organisms, including Pseudomonas aeruginosa. Las and Rhl are two major quorum-sensing components, and they are regulated by their corresponding autoinducers, N-3-oxododecanoyl homoserine lactone (3-oxo-C12-HSL) and N-butyryl-L-homoserine lactone (C4-HSL). Recent progress has demonstrated the potential of quorum-sensing molecules, especially 3-oxo-C12-HSL, for modulation of the host immune system. Here we show the specific ability of 3-oxo-C12-HSL to induce apoptosis in certain types of cells. When bone marrow-derived macrophages were incubated with synthetic 3-oxo-C12-HSL, but when they were incubated not C4-HSL, significant loss of viability was observed in a concentration (12 to 50 µM)- and incubation time (1 to 24 h)-dependent manner. The cytotoxic activity of 3-oxo-C12-HSL was also observed in neutrophils and monocytic cell lines U-937 and P388D1 but not in epithelial cell lines CCL-185 and HEp-2. Cells treated with 3-oxo-C12-HSL revealed morphological alterations indicative of apoptosis. Acceleration of apoptosis in 3-oxo-C12-HSL-treated cells was confirmed by multiple criteria (caspases 3 and 8, histone-associated DNA fragments, phosphatidylserine expression). Structure-activity correlation experiments demonstrated that the fine structure of 3-oxo-C12-HSL, the HSL backbone, and side chain length are required for maximal activity. These data suggest that Pseudomonas 3-oxo-C12-HSL specifically promotes induction of apoptosis, which may be associated with 3-oxo-C12-HSL-induced cytotoxicity in macrophages and neutrophils. Our data suggest that the quorum-sensing molecule 3-oxo-C12-HSL has critical roles in the pathogenesis of P. aeruginosa infection, not only in the induction of bacterial virulence factors but also in the modulation of host responses.

* Corresponding author. Mailing address: Department of Microbiology, Toho University School of Medicine, 5-21-16 Ohmorinishi, Ohtaku, Tokyo 143-8540, Japan. Phone: 81-3-3762-4151, ext. 2396. Fax: 81-3-5493-5415. E-mail: kazu{at}med.toho-u.ac.jp.

Editor: B. B. Finlay

Infection and Immunity, October 2003, p. 5785-5793, Vol. 71, No. 10
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.10.5785-5793.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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