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Infection and Immunity, January 2004, p. 269-276, Vol. 72, No. 1
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.1.269-276.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Tumor Necrosis Factor Alpha Enhances Actinobacillus actinomycetemcomitans Leukotoxin-Induced HL-60 Cell Apoptosis by Stimulating Lymphocyte Function-Associated Antigen 1 Expression{dagger}

Noboru Yamaguchi,1* Chie Kubo,1 Yoshikazu Masuhiro,2 Edward T. Lally,3 Toshihiko Koga,1,{ddagger} and Shigemasa Hanazawa2

Department of Preventive Dentistry,1 Division of Oral Infectious Diseases and Immunology, Kyushu University Faculty of Dental Science, Fukuoka 812-8582, Japan,2 Leon Levy Research Center for Oral Biology, University of Pennsylvania School of Dental Medicine, Philadelphia, Pennsylvania 19104-60023

Received 2 July 2003/ Returned for modification 29 August 2003/ Accepted 15 October 2003

We demonstrated previously that Actinobacillus actinomycetemcomitans leukotoxin (Ltx) is greatly able to induce apoptotic signaling in cells that are positive for lymphocyte function-associated antigen 1 (LFA-1), a cell receptor of Ltx. We investigated in this study whether inflammatory cytokines can regulate apoptosis of human leukemic HL-60 cells induced by Ltx. Of the cytokines tested, tumor necrosis factor alpha (TNF-{alpha}) significantly enhanced the Ltx-induced cell apoptosis. Northern and Western blotting analyses showed that TNF-{alpha} enhanced the expression of CD11a in the cells at both the mRNA and protein levels but did not do so for CD18 expression. TNF-{alpha} also enhanced the binding of Ltx to the cells. We also observed by measuring the mitochondrial transmembrane potential and the generation of superoxide anion that the cytokine enhanced Ltx-induced apoptosis in HL-60 cells. In addition, interleukin-1ß significantly enhanced Ltx-induced cell apoptosis, although the enhancing activity was lower than that of TNF-{alpha}. These stimulatory effects of both cytokines were also observed for human polymorphonuclear leukocytes. The ability of TNF-{alpha} to increase cell susceptibility to Ltx could be inhibited by preincubation of the cells with a monoclonal antibody against TNF receptor 1 but not by preincubation of the cells with a monoclonal antibody against anti-TNF receptor 2. Furthermore, the results of an assay of caspase 3 intracellular activity (PhiPhiLuxG1D2) showed that Ltx-induced caspase 3 activation was completely neutralized by CD18 antibody treatment, although significant neutralization was also observed with anti-CD11a antibody. Taken together, the results of the present study indicate that TNF-{alpha} acts as a potent stimulator of Ltx-induced HL-60 cell apoptosis via TNF receptor 1-mediated upregulation of LFA-1 expression.

* Corresponding author. Mailing address: Department of Preventive Dentistry, Kyushu University Faculty of Dental Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. Phone: 81-92-642-6423. Fax: 81-92-642-6354. E-mail: nyama{at}dent.kyushu-u.ac.jp.

{dagger} Dedicated to the memory of Toshihiko Koga.

Editor: J. T. Barbieri

{ddagger} Deceased.

Infection and Immunity, January 2004, p. 269-276, Vol. 72, No. 1
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.1.269-276.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Dileepan, T., Kachlany, S. C., Balashova, N. V., Patel, J., Maheswaran, S. K. (2007). Human CD18 Is the Functional Receptor for Aggregatibacter actinomycetemcomitans Leukotoxin. Infect. Immun. 75: 4851-4856 [Abstract] [Full Text]  


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