IAI Accepts, published online ahead of print on 27 May 2008

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Infect. Immun. doi:10.1128/IAI.00407-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Distinct Isoforms of Phospholipase A₂ mediate the ability of Salmonella enterica serotype Typhimurium and Shigella flexneri to induce the transepithelial migration of neutrophils

Karen L. Mumy, Jeffrey D. Bien, Michael A. Pazos, Karsten Gronert, Bryan P. Hurley, and Beth A. McCormick^*

Mucosal Immunology Laboratory, Massachusetts General Hospital, Charlestown, MA; The Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, MA; and the University of California, Berkeley, Center for Eye Disease and Development School of Optometry, Berkeley, CA

^* To whom correspondence should be addressed. Email: mccormic{at}helix.mgh.harvard.edu.

Salmonella and Shigella are responsible for millions of cases of enteric disease each year worldwide. While these pathogens have evolved distinct strategies for interacting with the human intestinal epithelium, they both induce significant proinflammatory responses that result in massive transepithelial migration of neutrophils across the intestinal mucosa. It has previously been shown with Salmonella enterica serotype Typhimurium that the process of neutrophil transmigration is mediated in part by the secretion of hepoxilin A₃ (HXA₃), a potent neutrophil chemoattractant, from the apical surface of infected model intestinal epithelial. This study confirms that HXA₃ is also secreted in response to infection by Shigella flexneri, and that it is produced by a pathway involving 12/15-lipoxygenase (LOX) and that S. typhimurium and S. flexneri share certain elements in the mechanism(s) that underlie the otherwise separate signal transduction pathways that are engaged to induce PMN transepithelial migration (PKC and ERK1/2, respectively). PMN transepithelial migration in response to infection with S. flexneri was dependent on 12/15 LOX activity, the enzyme responsible for the initial metabolism of arachidonic acid to HXA₃. Probing further into this pathway we also found that S. typhimurium and S. flexneri activate different subtypes of phospholipase A₂, a critical enzyme involved in the liberation of arachidonic acid from cellular membranes. Thus, although S. typhimurium and S. flexneri utilize different mechanisms for triggering the induction of PMN transepithelial migration, we found that their reliance on 12/15-LOX is conserved, suggesting that enteric pathogens may ultimately stimulate similar pathways for the synthesis and release HXA₃.

This article has been cited by other articles:

• Pazos, M., Siccardi, D., Mumy, K. L., Bien, J. D., Louie, S., Shi, H. N., Gronert, K., Mrsny, R. J., McCormick, B. A. (2008). Multidrug Resistance-Associated Transporter 2 Regulates Mucosal Inflammation by Facilitating the Synthesis of Hepoxilin A3. J. Immunol. 181: 8044-8052 [Abstract] [Full Text]