Journal of Leukocyte Biology
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A more recent version of this article appeared on December 1, 2007

Published online before print August 27, 2007
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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0806528

Received for publication August 22, 2006.
Revised July 27, 2007.
Accepted for publication August 7, 2007.

Article

Neutrophil transepithelial migration in response to the chemoattractant fMLP but not C5a is phospholipase D-dependent and related to the use of CD11b/CD18

Svetlana O. Carrigan *, Desmond B. S. Pink {dagger}, and Andrew W. Stadnyk *{dagger}@

Departments of *Microbiology and Immunology and {dagger}Pediatrics, and the Dalhousie Inflammation Group, Dalhousie University, Halifax, Nova Scotia, Canada

@ To whom correspondence should be addressed. E-mail: astadnyk{at}dal.ca.


  Abstract

In Crohn's disease and ulcerative colitis patients, the numbers of neutrophils recovered from stool directly correlates with the severity of disease, implying that neutrophils in the lumen contribute to the tissue destruction; therefore, it is important to understand the mechanisms behind transintestinal epithelial migration. Neutrophil transintestinal epithelial migration to fMLP is appreciated to be CD11b/CD18 integrin (Mac-1)-dependent, while we recently reported that migration to C5a is Mac-1-independent. Here, we investigated whether phospholipase D (PLD), a signaling molecule linked to chemoattractant activation of neutrophils, is necessary for both Mac-1-dependent and Mac-1-independent migration. Both fMLP and C5a increased neutrophil expression of the Mac-1 activation epitope, indicating PLD was activated. This up-regulation was dose-dependently prevented by incubation of neutrophils in 1-butanol, an inhibitor of PLD activity. Despite this effect on Mac-1, 1-butanol did not prevent neutrophil migration across acellular filters. Incubation in 1-butanol did inhibit fMLP but not C5a-mediated migration across intestinal epithelial cell monolayers, showing that transepithelial migration to fMLP but not C5a is dependent on PLD. The addition of phosphatidic acid, a reaction product of PLD, partially restored fMLP-mediated transepithelial migration in the presence of 1-butanol but not the migration of Mac-1-deficient neutrophil-differentiated HL-60 cells. Thus PLD control overexpression of the Mac-1 activation epitope is critical for neutrophil migration to fMLP but not C5a. Moreover, as PLD controls other neutrophil functions, such as the oxidative response, degranulation, and protease release, we could exclude these functions as being important in neutrophil transepithelial migration to C5a.

Key Words: leukocyte • mucosa • chemotaxis • signal transduction • lipid mediators






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Copyright © 2007 by the Society for Leukocyte Biology.