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First published online January 10, 2008
doi: 10.1242/10.1242/jcs.020412

Journal of Cell Science 121, 205-214 (2008)
Published by The Company of Biologists 2008
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Research Article

PI3K accelerates, but is not required for, neutrophil chemotaxis to fMLP

Bryan Heit1, Lixin Liu2, Pina Colarusso1, Kamal D. Puri3 and Paul Kubes1,*

1 Immunology Research Group, Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta, T2N 4N1, Canada
2 Department of Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 5E5, Canada
3 Calistoga Pharmaceuticals, Seattle, WA 98121, USA

* Author for correspondence (e-mail: pkubes{at}ucalgary.ca)

Accepted 11 October 2007

PI3K activity, resulting in the accumulation of PIP3 along the leading edge of a chemotaxing cell, has been proposed to be an indispensable signaling event that is required for cells to undergo chemotaxis to endogenous and exogenous chemoattractants. Some studies have suggested that this might be the case for chemoattractants such as IL8, whereas chemotaxis to other stimuli, such as the bacterial peptide N-formyl-methionyl-leucyl-phenylalanine (fMLP), might occur normally in the absence of PI3K activity. Herein, we systematically analyze the role of PI3K in mediating chemotaxis to fMLP, both in vitro and in vivo. Using short- and long-term in vitro assays, as well as an in vivo chemotaxis assay, we investigated the importance of PI3K in response to the prototypic chemoattractant fMLP. Exposure of neutrophils to fMLP induced an immediate polarization, which resulted in directional migration towards fMLP within 2-3 minutes. PI3K-inhibited cells also polarized and migrated in a directional fashion towards fMLP; however, this process was delayed by ~15 minutes, demonstrating that PI3K accelerates the initial response to fMLP, but an alternative pathway replaces PI3K over time. By contrast, p38-MAPK-inhibited cells, or cells lacking MK2, were unable to polarize in response to fMLP. Long-term chemotaxis assays using a pan-PI3K inhibitor, a PI3K{delta}-specific inhibitor or PI3K{gamma}-knockout neutrophils, demonstrated no role for PI3K in mediating chemotaxis to fMLP, regardless of the steepness of the fMLP gradient. Similar results were observed in vivo, with PI3K{gamma}–/– cells displaying a delayed, but otherwise normal, chemotactic response to gradients of fMLP. Together, these data demonstrate that, although PI3K can enhance early responses to the bacterial chemoattractant fMLP, it is not required for migration towards this chemoattractant.

Key words: PI3K, p38 MAPK, Chemotaxis, Neutrophil, Recruitment, Migration




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