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Published online before print October 5, 2006

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(Journal of Leukocyte Biology. 2007;81:229-237.)
© 2007 by Society for Leukocyte Biology

Aspartic protease and caspase 3/7 activation are central for macrophage apoptosis following infection with Escherichia coli

Lee Albee^*,1, Bo Shi and Harris Perlman^*,2

^* Saint Louis University, School of Medicine, Department of Molecular Microbiology and Immunology, Saint Louis, Missouri, USA; and
Northwestern University, Feinberg School of Medicine, Division of Rheumatology, Chicago, Illinois, USA

²Correspondence: Saint Louis University, School of Medicine, Department of Molecular Microbiology and Immunology, 1402 South Grand Blvd., St. Louis, MO 63104, USA. E-mail: perlmanh{at}slu.edu

Macrophages are vital for host defense against microbial infections. We have previously shown that infection of macrophages with a nonpathogenic strain of Escherichia coli induces apoptosis rapidly. Here, we demonstrate that infection of macrophages results in the activation of caspases prior to the induction of the intrinsic apoptosis pathway. Caspases 9 and 3 are activated prior to the release of intermembrane mitochondrial protein cytochrome C into the cytosol in infected macrophages. Treatment with an inhibitor to caspase 9 has no effect on the death of macrophages and does not prevent activation of the downstream effector caspase 3/7. In contrast, an inhibitor to caspase 3/7 reduces cell death in E. coli-infected macrophages. Although caspase 9 is not required, activation of aspartic proteases, of which cathepsin D is one of the central members, is essential for activation of caspase 3/7. Treatment with pepstatin A, an inhibitor of aspartic proteases, markedly diminishes the activation of cathepsin D and caspase 3/7 and reduces death in E. coli-infected macrophages. Collectively, these data suggest that cathepsin D activation of caspase 3/7 may be required for inducing one of the death pathways elicited by E. coli.

Key Words: bacteria • lysosomal • mitochondria • Bcl-2

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