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Infection and Immunity, January 2005, p. 453-458, Vol. 73, No. 1
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.1.453-458.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Abundant Secretion of Bioactive Interleukin-1ß by Human Macrophages Induced by Actinobacillus actinomycetemcomitans Leukotoxin

Divisions of Periodontology,¹ Oral Microbiology,² Oral Cell Biology, Department of Odontology, Faculty of Medicine, Umeå University, Umeå, Sweden,³ School of Dentistry, Aristotle University of Thessaloniki, Thessaloniki, Greece⁴

Received 21 May 2004/ Returned for modification 22 August 2004/ Accepted 11 September 2004

Actinobacillus actinomycetemcomitans produces a leukotoxin that selectively kills human leukocytes. Recently, we reported that macrophages are highly sensitive to leukotoxin and that their lysis involves activation of caspase 1. In this study, we show that leukotoxin also induces the production and release of proinflammatory cytokines from human macrophages. The macrophages were challenged with leukotoxin or lipopolysaccharide (LPS) from A. actinomycetemcomitans or LPS from Escherichia coli, and the production and secretion of interleukin-1ß (IL-1ß), IL-6, and tumor necrosis factor alpha (TNF-) were determined at the mRNA and protein levels by reverse transcription-PCR and enzyme-linked immunosorbent assay, respectively. Leukotoxin (1 to 30 ng/ml) induced abundant production and secretion of IL-1ß, while the effects on IL-6 and TNF- production were limited. Leukotoxin (1 ng/ml) caused a 10-times-higher release of IL-1ß than did LPS (100 ng/ml). The secreted IL-1ß was mainly the bioactive 17-kDa protein. At higher concentrations (>30 ng/ml), leukotoxin caused secretion of mainly inactive cytokine, the 31-kDa pro-IL-1ß. The presence of specific antibodies to IL-1ß or of a caspase 1 inhibitor blocked the secretion and production of the cytokine. Supernatants of leukotoxin-challenged macrophages stimulated bone resorption when tested in a mouse calvarial model. The activity could be blocked by an IL-1 receptor antagonist or specific antibodies to IL-1ß. We concluded that A. actinomycetemcomitans leukotoxin can trigger abundant production and secretion of bioactive IL-1ß by human macrophages, which is mediated by activation of caspase 1.

Editor: J. D. Clements

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