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However, the molecular mechanisms responsible for host cell death remained largely unknown. Here we demonstrate that<jats:italic>L. interrogans<\/jats:italic>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<jats:italic>c<\/jats:italic>from mitochondria was detectable. Inhibition of caspase-8 impaired<jats:italic>L. interrogans<\/jats:italic>-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<jats:italic>L. interrogans<\/jats:italic>-induced apoptosis in macrophages is mediated by caspase-3 and -6 activation through a FADD-caspase-8-dependent pathway, independently of mitochondrial cytochrome<jats:italic>c<\/jats:italic>-caspase-9-dependent signaling.<\/jats:p>","DOI":"10.1128\/iai.00914-08","type":"journal-article","created":{"date-parts":[[2008,11,25]],"date-time":"2008-11-25T01:50:29Z","timestamp":1227577829000},"page":"799-809","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":75,"title":["<i>Leptospira interrogans<\/i>Induces Apoptosis in Macrophages via Caspase-8- and Caspase-3-Dependent Pathways"],"prefix":"10.1128","volume":"77","author":[{"given":"Dandan","family":"Jin","sequence":"first","affiliation":[{"name":"School of Life Sciences"},{"name":"Department of Medical Microbiology and Parasitology, School of Medicine, Zhejiang University, 388 Yu-Hang-Tang Road, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David M.","family":"Ojcius","sequence":"additional","affiliation":[{"name":"School of Natural Sciences, University of California, Merced, California 95344"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dexter","family":"Sun","sequence":"additional","affiliation":[{"name":"New York Presbyterian Hospital and Hospital for Special Surgery, Weill Medical College, Cornell University SinoUnited Health, 943 Lexington Avenue, New York, New York 10021"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiyan","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Parasitology, School of Medicine, Zhejiang University, 388 Yu-Hang-Tang Road, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yihui","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Parasitology, School of Medicine, Zhejiang University, 388 Yu-Hang-Tang Road, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yafei","family":"Mao","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Parasitology, School of Medicine, Zhejiang University, 388 Yu-Hang-Tang Road, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Parasitology, School of Medicine, Zhejiang University, 388 Yu-Hang-Tang Road, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cdd.4400733"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.69.3.1287-1297.2001"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00460-06"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(03)00830-2"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.micpath.2006.11.002"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.01866-06"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cdd.4401065"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.femsre.2003.10.004"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(04)00046-7"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1002\/path.1711280403"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1006\/phrs.2001.0885"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1053\/jinf.2001.0836"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.68.1.383"},{"key":"e_1_3_2_15_2","first-page":"45","volume":"26","year":"1965","unstructured":"Ellinghausen, H. 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