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Published online before print July 15, 2003

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© 2003 by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.1202586

Received for publication December 1, 2002.
Revised April 17, 2003.
Accepted for publication April 23, 2003.

Article

Differential effects of invasion by and phagocytosis of Salmonella typhimurium on apoptosis in human macrophages: potential role of Rho-GTPases and Akt

Maria Forsberg ^*, Robert Blomgran ^*, Maria Lerm ^*, Eva Särndahl , Said M. Sebti , Andrew Hamilton , Olle Stendahl ^*, and Limin Zheng ^*@

Divisions of *Medical Microbiology, IMK, and Cell Biology, IBK, Linköping University, Sweden; Drug Discovery Program, H. Lee Moffitt Cancer Center & Research Institute, Department of Oncology, University of South Florida, Tampa; and Department of Chemistry, Yale University, New Haven, Connecticut

	Abstract

In addition to direct activation of caspase-1 and induction of apoptosis by SipB, invasive Salmonella stimulates multiple signaling pathways that are key regulators of host cell survival. Nevertheless, little is known about the relative contributions of these pathways to Salmonella-mediated death of macrophages. We studied human monocytic U937 cells and found that apoptosis was induced by invading wild-type Salmonella typhimurium but not by phagocytosed, serum-opsonized, noninvasive Salmonella mutants. Pretreating U937 cells with inhibitors of tyrosine kinases or phosphatidylinositol-3 kinase (PI-3K) completely blocked phagocytosis of opsonized Salmonella mutants but did not affect invasion by wild-type Salmonella or the apoptosis caused by invasion. However, pretreatment with GGTI-298, a geranylgeranyltransferase-1 inhibitor that prevents prenylation of Cdc42 and Rac1, suppressed Salmonella-induced apoptosis by 70%. Transduction of Tat fusion constructs containing dominant-negative Cdc42 or Rac1 significantly inhibited Salmonella-induced cell death, indicating that the cytotoxicity of Salmonella requires activation of Cdc42 and Rac. In contrast to phagocytosis of opsonized bacteria, invasion by S. typhimurium stimulated Cdc42 and Rac1, regardless of the activities of tyrosine- or PI-3K. Moreover, Salmonella infection activated Akt protein in a tyrosine-kinase or PI-3K-dependent manner, and a reduced expression of Akt by antisense transfection rendered the cells more sensitive to apoptosis induced by opsonized Salmonella. These results indicate that direct activation of Cdc42 and Rac1 by invasive Salmonella is a prerequisite of Salmonella-mediated death of U937 cells, whereas the simultaneous activation of Akt by tyrosine kinase and PI-3K during receptor-mediated phagocytosis protects cells from apoptosis.

Key Words: macrophages • bacterial apoptosis • signal transduction

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