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Infection and Immunity, July 2006, p. 4104-4113, Vol. 74, No. 7
0019-9567/06/$08.00+0     doi:10.1128/IAI.02045-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

The Type III Pseudomonal Exotoxin U Activates the c-Jun NH2-Terminal Kinase Pathway and Increases Human Epithelial Interleukin-8 Production

Alayne Cuzick,1,{dagger} Fiona R. Stirling,2 Susan L. Lindsay,2 and Thomas J. Evans2*

Department of Infectious Diseases, Faculty of Medicine, Imperial College, London, United Kingdom,1 Division of Immunology, Infection and Inflammation, Faculty of Medicine, University of Glasgow, Glasgow, United Kingdom2

Received 20 December 2005/ Returned for modification 30 January 2006/ Accepted 19 April 2006

Microbial interactions with host cell signaling pathways are key determinants of the host cell response to infection. Many toxins secreted by bacterial type III secretion systems either stimulate or inhibit the host inflammatory response. We investigated the role of type III secreted toxins of the lung pathogen Pseudomonas aeruginosa in the inflammatory response of human respiratory epithelial cells to infection. Using bacteria with specific gene deletions, we found that interleukin-8 production by these cells was almost entirely dependent on bacterial type III secretion of exotoxin U (ExoU), a phospholipase, although other bacterial factors are involved. ExoU activated the c-Jun NH2-terminal kinase pathway, stimulating the phosphorylation and activation of mitogen-activated kinase kinase 4, c-Jun NH2-terminal kinase, and c-Jun. This in turn increased levels of transcriptionally competent activator protein-1. Although this pathway was dependent on the lipase activity of ExoU, it was independent of cell death. Activation of mitogen-activated kinase signaling by ExoU in this fashion is a novel mechanism by which a bacterial product can initiate a host inflammatory response, and it may result in increased epithelial permeability and bacterial spread.

* Corresponding author. Mailing address: Division of Immunology, Infection and Inflammation, University of Glasgow, Western Infirmary, Glasgow G11 6NT, United Kingdom. Phone: 44 141 211 2591. Fax: 44 141 337 3217. E-mail: t.j.evans{at}udcf.gla.ac.uk.

Editor: J. T. Barbieri

{dagger} Present address: Rothamsted Research, Plant-Pathogen Interactions Division, Harpenden, Hertfordshire AL5 2JQ, United Kingdom.

Infection and Immunity, July 2006, p. 4104-4113, Vol. 74, No. 7
0019-9567/06/$08.00+0     doi:10.1128/IAI.02045-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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