IngentaConnect Differentiation of human monocytic cell lines confers susceptibil...

Authors: Altaf Kassam¹; Sandy D. Der²; Jeremy Mogridge

Source: Cellular Microbiology, Volume 7, Number 2, February 2005 , pp. 281-292(12)

Abstract:

Summary

Anthrax lethal toxin (LT) is comprised of protective antigen and lethal factor. Lethal factor enters mammalian cells in a protective antigen-dependent process and cleaves mitogen-activated protein kinase kinases. Although LT has no observable effect on many cell types, it causes necrosis in macrophages derived from certain mouse strains and apoptosis in activated mouse macrophages. In this study, we observed that LT treatment of three different human monocytic cell lines U-937, HL-60 and THP-1 did not induce cell death. Cells did become susceptible to the toxin, however, after differentiation into a macrophage-like state. Treatment with LT resulted in decreased phosphorylation of p38, ERK1/2 and JNK in both undifferentiated and differentiated HL-60 cells, suggesting that the change in susceptibility does not result from differences in toxin delivery or substrate cleavage. Death of differentiated HL-60 cells was accompanied by chromosome condensation and DNA fragmentation, but was not inhibited by the pan-caspase inhibitor Z-VAD-FMK. In addition, we observed that the macrophage differentiation process could be inhibited by LT. Our results indicate that LT-mediated death of mouse and human macrophages may occur through distinct processes and that the differentiation state of human cells can determine susceptibility or resistance to LT.

Document Type: Research article

DOI: 10.1111/j.1462-5822.2004.00458.x

Affiliations: 1: Department of Laboratory Medicine and Pathobiology, 2: Program in Proteomics and Bioinformatics, University of Toronto, Toronto M5S 1A8,

You have access to the full text article on a website external to Ingentaconnect.

Please click here to view this article on InterScience.

You may be required to register and activate access on InterScience before you can obtain the full text. If you have any queries please contact onlinehelp@oxon.blackwellpublishing.com

Differentiation of human monocytic cell lines confers susceptibility to Bacillus anthracis lethal toxin