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Papers In Press, published online ahead of print January 30, 2002
Department of Biotechnology Laboratory, University of British Columbia, Vancouver, BC V6T 1Z3
Corresponding Author: bfinlay{at}interchange.ubc.ca
Host responses during the later stages of Salmonella-macrophage interactions are critical to controlling infection but have not been well characterized. After 24 h of infection, nearly half of interferon-
J. Biol. Chem, 10.1074/jbc.M110649200
Submitted on November 6, 2001
Revised on January 29, 2002
Accepted on January 29, 2002
Macrophages inhibit Salmonella Typhimurium replication through MEK/ERK kinase and phagocyte NADPH oxidase activities
primed murine RAW 264.7 macrophage-like cells infected by Salmonella enterica serovar Typhimurium contained filamentous bacteria. Bacterial filamentation indicates a defect in completing replication and has been previously observed in bacteria responding to a variety of stresses. To understand whether macrophage gene expression was responsible for this effect on S. Typhimurium replication, we used gene arrays to profile interferon- primed RAW 264.7 cell gene expression following infection. We observed an increase in MEK1 kinase mRNA at 8 h, an increase in MEK protein at 24 h, and measured phosphorylation of MEK’s downstream target kinase, ERK1/2, throughout the 24 h infection period. Treatment of cells with MEK kinase inhibitors significantly reduced numbers of filamentous bacteria observed within macrophages after 24 h and increased the number of intracellular CFU. Phagocyte NADPH oxidase inhibitors and antioxidants also significantly reduced bacterial filamentation. Either MEK kinase or phagocyte oxidase inhibitors could be added 4-8 h after infection and still significantly decrease bacterial filamentation. Oxidase activity appears to mediate bacterial filamentation in parallel to MEK kinase signaling, while inducible nitric oxide synthase inhibitors had no significant effect on bacterial morphology. In summary, S. Typhimurium infection of interferon- primed macrophages triggers a MEK kinase cascade at later infection times and both MEK kinase and phagocyte NADPH oxidase activity impair bacterial replication. These two signaling pathways mediate a host bacteriostatic pathway and may play an important role in innate host defense against intracellular pathogens.
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