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Infection and Immunity, September 1998, p. 4474-4483, Vol. 66, No. 9
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Actinobacillus actinomycetemcomitans Leukotoxin Induces Apoptosis in HL-60 Cells

Jonathan Korostoff,* Jian Fei Wang, Irene Kieba, Mark Miller, Bruce J. Shenker, and Edward T. Lally

Leon Levy Research Center for Oral Biology, University of Pennsylvania, Philadelphia, Pennsylvania, 19104-6002

Received 2 April 1998/Returned for modification 6 May 1998/Accepted 7 June 1998

Actinobacillus actinomycetemcomitans leukotoxin (Ltx) is a member of the repeats-in-toxin (RTX) family of pore-forming toxins and kills human immune cells. Currently, it remains unclear whether toxin-mediated killing of target cells involves the induction of necrosis or apoptosis. Therefore, the goal of this investigation was to determine whether Ltx is capable of causing apoptotic cell death in toxin-sensitive promyelocytic HL-60 cells. Multiparameter flow cytometric analysis of toxin-treated cells stained with Hoechst 33258 (or 33342) and 7-aminoactinomycin D allowed us to identify four populations: viable cells, early apoptotic cells, late apoptotic and/or secondarily necrotic cells, and a final population that was composed of cellular debris. Compared with control cells, HL-60 cells treated with Ltx exhibited a gradual decrease in forward light scatter with a coincident increase in side light scatter, indicative of a decrease in cell size and organelle condensation, respectively. Additional experiments demonstrated that Ltx-treated cells showed evidence of internucleosomal DNA fragmentation and phosphatidylserine translocation. The results of our studies clearly demonstrate that Ltx can kill HL-60 cells by inducing apoptosis. We hypothesize that elimination of acute inflammatory cells via this mechanism plays a critical role in the pathogenesis of diseases caused by A. actinomycetemeomitans.

* Corresponding author. Mailing address: Leon Levy Research Center for Oral Biology, University of Pennsylvania, 4010 Locust St., Philadelphia, PA 19104-6002. Phone: (215) 573-3965. Fax: (215) 898-8385. E-mail: jkorosto{at}pobox.upenn.edu.

Infection and Immunity, September 1998, p. 4474-4483, Vol. 66, No. 9
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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