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J. Cell Biol. 159 (1): 91-102

Copyright © 2002 by the Rockefeller University Press.


An intracellular signaling hierarchy determines direction of migration in opposing chemotactic gradients

Bryan Heit, Samantha Tavener, Eko Raharjo, and Paul Kubes

Immunology Research Group, Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary, Alberta T2N 4N1, Canada

Address correspondence to Paul Kubes, Immunology Research Group, University of Calgary, 3330 Hospital Dr. NW, Alberta T2N 4N1, Canada. Tel.: (403) 220-8558. Fax: (403) 283-1267. E-mail: pkubes{at}

Abstract: Neutrophils must follow both endogenous and bacterial chemoattractant signals out of the vasculature and through the interstitium to arrive at a site of infection. By necessity, in the setting of multiple chemoattractants, the neutrophils must prioritize, favoring end target chemoattractants (e.g., fMLP and C5a) emanating from the site of infection over intermediary endogenous chemoattractants (e.g., IL-8 and LTB4) encountered en route to sites of infection. In this study, we propose a hierarchical model of two signaling pathways mediating the decision-making process of the neutrophils, which allows end target molecules to dominate over intermediary chemoattractants. In an under agarose assay, neutrophils predominantly migrated toward end target chemoattractants via p38 MAPK, whereas intermediary chemoattractant-induced migration was phosphoinositide 3-kinase (PI3K)/Akt dependent. When faced with competing gradients of end target and intermediary chemoattractants, Akt activation was significantly reduced within neutrophils, and the cells migrated preferentially toward end target chemoattractants even at 1/1,000th that of intermediary chemoattractants. End target molecules did not require chemotactic properties, since the p38 MAPK activator, LPS, also inhibited Akt and prevented migration to intermediary chemoattractants. p38 MAPK inhibitors not only reversed this hierarchy, such that neutrophils migrated preferentially toward intermediary chemoattractants, but also allowed neutrophils to be drawn out of a local end target chemoattractant environment and toward intermediary chemoattractants unexpectedly in an exaggerated (two- to fivefold) fashion. This was entirely related to significantly increased magnitude and duration of Akt activation. Finally, end target chemoattractant responses were predominantly Mac-1 dependent, whereas nondominant chemoattractants used primarily LFA-1. These data provide support for a two pathway signaling model wherein the end target chemoattractants activate p38 MAPK, which inhibits intermediary chemoattractant-induced PI3K/Akt pathway, establishing an intracellular signaling hierarchy.

Key Words: p38 MAPK; PI3K gamma; chemotaxis; neutrophils; signal transduction

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Two Phases of Actin Polymerization Display Different Dependencies on PI(3,4,5)P3 Accumulation and Have Unique Roles during Chemotaxis.
L. Chen, C. Janetopoulos, Y. E. Huang, M. Iijima, J. Borleis, and P. N. Devreotes (2003)
Mol. Biol. Cell 14, 5028-5037
   Abstract »    Full Text »    PDF »
In Vivo Impairment of Neutrophil Recruitment during Lentivirus Infection.
P. Kubes, B. Heit, G. van Marle, J. B. Johnston, D. Knight, A. Khan, and C. Power (2003)
J. Immunol. 171, 4801-4808
   Abstract »    Full Text »    PDF »
Neutrophil activation by fMLP regulates FOXO (forkhead) transcription factors by multiple pathways, one of which includes the binding of FOXO to the survival factor Mcl-1.
L. J. Crossley (2003)
J. Leukoc. Biol. 74, 583-592
   Abstract »    Full Text »    PDF »
Mechanisms of Leukotriene B4-Triggered Monocyte Adhesion.
E. B. Friedrich, A. M. Tager, E. Liu, A. Pettersson, C. Owman, L. Munn, A. D. Luster, and R. E. Gerszten (2003)
Arterioscler Thromb Vasc Biol 23, 1761-1767
   Abstract »    Full Text »    PDF »
Reactivation of Formyl Peptide Receptors Triggers the Neutrophil NADPH-oxidase but Not a Transient Rise in Intracellular Calcium.
J. Bylund, A. Bjorstad, D. Granfeldt, A. Karlsson, C. Woschnagg, and C. Dahlgren (2003)
J. Biol. Chem. 278, 30578-30586
   Abstract »    Full Text »    PDF »
Measuring Chemotaxis and Chemokinesis: The Under-Agarose Cell Migration Assay.
B. Heit and P. Kubes (2003)
Sci. STKE 2003, pl5
   Abstract »    Full Text »    PDF »

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