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Infection and Immunity, August 2003, p. 4382-4388, Vol. 71, No. 8
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.8.4382-4388.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Human Alveolar Macrophages Infected by Virulent Bacteria Expressing SipB Are a Major Source of Active Interleukin-18

Carolina Obregon,1 Donatus Dreher,1 Menno Kok,2 Laurence Cochand,1 Gitahi S. Kiama,3,4 and Laurent P. Nicod1*

Division of Pneumology, University Hospital of Geneva,1 Department of Genetics and Microbiology, University of Geneva, Geneva,2 Institute of Anatomy, University of Bern, Bern, Switzerland,3 Department of Veterinary Anatomy, University of Nairobi, Nairobi, Kenya4

Received 3 October 2002/ Returned for modification 26 November 2002/ Accepted 23 May 2003

Recent publications have demonstrated that the protease caspase-1 is responsible for the processing of pro-interleukin 18 (IL-18) into the active form. Studies on cell lines and murine macrophages have shown that the bacterial invasion factor SipB activates caspase-1, triggering cell death. Thus, we investigated the role of SipB in the activation and release of IL-18 in human alveolar macrophages (AM), which are the first line of defense against inhaled pathogens. Under steady-state conditions, AM are a more important source of IL-18 than are dendritic cells (DC) and monocytes. Cytokine production by AM and DC was compared after both types of cells had been infected with a virulent strain of Salmonella enterica serovar Typhimurium and an isogenic sipB mutant, which were used as an infection model. Infection with virulent Salmonella led to marked cell death with features of apoptosis while both intracellular activation and release of IL-18 were demonstrated. In contrast, the sipB mutant did not induce such cell death or the release of active IL-18. The specific caspase-1 inhibitor Ac-YVAD-CMK blocked the early IL-18 release in AM infected with the virulent strain. However, the type of Salmonella infection did not differentially regulate IL-18 gene expression. We concluded that the bacterial virulence factor SipB plays an essential posttranslational role in the intracellular activation of IL-18 and the release of the cytokine in human AM.

* Corresponding author. Mailing address: Division de Pneumologie, Hôpital Universitaire de Genève, 24, rue Micheli du Crest, 1211 Geneva 14, Switzerland. Phone: 41 22 3729546. Fax: 41 22 3729929. E-mail: Laurent.Nicod{at}hcuge.ch.

Editor: F. C. Fang

Infection and Immunity, August 2003, p. 4382-4388, Vol. 71, No. 8
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.8.4382-4388.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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