Distinct isoforms of phospholipase A2 mediate the ability of Salmonella enterica serotype typhimurium and Shigella flexneri to induce the transepithelial migration of neutrophils

Infect Immun. 2008 Aug;76(8):3614-27. doi: 10.1128/IAI.00407-08. Epub 2008 May 27.


Salmonella spp. and Shigella spp. 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 A(3) (HXA(3); 8-hydroxy-11,12-epoxy-eicosatetraenoic acid), a potent neutrophil chemoattractant, from the apical surface of infected model intestinal epithelium. This study confirms that HXA(3) is also secreted in response to infection by Shigella flexneri, that it is produced by a pathway involving 12/15-lipoxygenase (12/15-LOX), and that S. enterica serovar Typhimurium and S. flexneri share certain elements in the mechanism(s) that underlies the otherwise separate signal transduction pathways that are engaged to induce polymorphonuclear leukocyte (PMN) transepithelial migration (protein kinase C and extracellular signal-regulated kinases 1 and 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 HXA(3). Probing further into this pathway, we also found that S. enterica serovar Typhimurium and S. flexneri activate different subtypes of phospholipase A(2), a critical enzyme involved in the liberation of arachidonic acid from cellular membranes. Thus, although S. enterica serovar 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 of HXA(3).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 8,11,14-Eicosatrienoic Acid / analogs & derivatives
  • 8,11,14-Eicosatrienoic Acid / metabolism
  • Arachidonate 12-Lipoxygenase / genetics
  • Arachidonate 12-Lipoxygenase / metabolism
  • Arachidonate 15-Lipoxygenase / genetics
  • Arachidonate 15-Lipoxygenase / metabolism
  • Cell Line
  • Cell Migration Assays, Leukocyte
  • Cell Movement / immunology*
  • Humans
  • Intestinal Mucosa / immunology
  • Intestinal Mucosa / microbiology
  • Isoenzymes
  • Neutrophils / immunology*
  • Phospholipases A2 / chemistry*
  • Phospholipases A2 / immunology*
  • Salmonella typhimurium / enzymology*
  • Salmonella typhimurium / immunology*
  • Shigella flexneri / enzymology*
  • Shigella flexneri / immunology*


  • Isoenzymes
  • 8-hydroxy-11,12-epoxyeicosa-5,9,14-trienoic acid
  • Arachidonate 12-Lipoxygenase
  • Arachidonate 15-Lipoxygenase
  • Phospholipases A2
  • 8,11,14-Eicosatrienoic Acid