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Infection and Immunity, February 2009, p. 799-809, Vol. 77, No. 2
0019-9567/09/$08.00+0     doi:10.1128/IAI.00914-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Leptospira interrogans Induces Apoptosis in Macrophages via Caspase-8- and Caspase-3-Dependent Pathways {triangledown}

Dandan Jin,1,2 David M. Ojcius,3 Dexter Sun,4 Haiyan Dong,2 Yihui Luo,2 Yafei Mao,2 and Jie Yan2*

School of Life Sciences,1 Department of Medical Microbiology and Parasitology, School of Medicine, Zhejiang University, 388 Yu-Hang-Tang Road, Hangzhou 310058, China,2 School of Natural Sciences, University of California, Merced, California 95344,3 New York Presbyterian Hospital and Hospital for Special Surgery, Weill Medical College, Cornell University SinoUnited Health, 943 Lexington Avenue, New York, New York 100214

Received 23 July 2008/ Returned for modification 7 September 2008/ Accepted 9 November 2008

Apoptosis of host cells plays an important role in modulating the pathogenesis of many infectious diseases. It has been reported that Leptospira interrogans, the causal agent of leptospirosis, induces apoptosis in macrophages and hepatocytes. However, the molecular mechanisms responsible for host cell death remained largely unknown. Here we demonstrate that L. interrogans induced apoptosis in a macrophage-like cell line, J774A.1, and primary murine macrophages in a time- and dose-dependent manner. Apoptosis was associated with the activation of cysteine aspartic acid-specific proteases (caspase-3, caspase-6, and caspase-8), the increased expression of Fas-associated death domain (FADD), and the cleavage of the caspase substrates poly(ADP-ribose) polymerase (PARP) and nuclear lamina protein (lamin A and lamin C). Caspase-9 was activated to a lesser extent, whereas no release of cytochrome c from mitochondria was detectable. Inhibition of caspase-8 impaired L. interrogans-induced caspase-3 and -6 activation, as well as PARP and lamin A/C cleavage and apoptosis, suggesting that apoptosis is initiated via caspase-8 activation. Furthermore, caspase-3 was required for the activation of caspase-6 and seemed to be involved in caspase-9 activation through a feedback amplification loop. These data indicate that L. interrogans-induced apoptosis in macrophages is mediated by caspase-3 and -6 activation through a FADD-caspase-8-dependent pathway, independently of mitochondrial cytochrome c-caspase-9-dependent signaling.

* Corresponding author. Mailing address: Department of Medical Microbiology and Parasitology, School of Medicine, Zhejiang University, 388 Yu-Hang-Tang Road, Hangzhou 310058, China. Phone: 86-571-88208297. Fax: 86-571-88208294. E-mail: med_bp{at}zju.edu.cn

{triangledown} Published ahead of print on 24 November 2008.

Editor: S. R. Blanke

Infection and Immunity, February 2009, p. 799-809, Vol. 77, No. 2
0019-9567/09/$08.00+0     doi:10.1128/IAI.00914-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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