Sci. STKE, 29 October 2002
Chemotaxis How Neutrophils Heed the Call
A neutrophil summoned to a site of infection is first attracted by chemokines like interleukin 8 (IL-8, an intermediary or host-derived chemoattractant). Once at the site of infection or tissue damage, the neutrophil then encounters chemoattractants from the end target, for example the bacterial product fMLP (formyl-methionyl-leucyl-phenylalanine). These attractant signals can be present in conflicting gradients, and proper movement of the neutrophil to its final target requires a preferential response to the signal from the end target. Heit et al. describe signaling circuitry that can explain how neutrophils process such complicated signals. Chemoattractant receptors can stimulate multiple intracellular signaling pathways, but the authors found that, in culture, exposure of human neutrophils to the intermediary chemoattractant IL-8 mainly stimulated signaling through the PI3K (phosphoinositide 3-kinase) pathway, whereas response to the end target compound fMLP was mediated largely by activation of the mitogen-activated protein kinase p38. Neutrophils will migrate toward either IL-8 or fMLP alone, but more telling was their response when simultaneously exposed to competing gradients of both chemoattractants. The cells preferentially migrated toward the end target fMLP even if concentrations of IL-8 were much larger. Unexpectedly, optimally effective concentrations of IL-8 actually enhanced migration in response to fMLP. The authors showed that signals from fMLP through p38 suppress activation of PI3K by IL-8, thus explaining the observed preferential response to fMLP. In fact, the hierarchy of the two attractants could be reversed if cells were exposed to a pharmacological inhibitor of p38. The enhanced response to fMLP in the presence of a competing gradient of IL-8 could also be explained by the authors' observation that exposure to IL-8 increased the number of fMLP receptors detected on the surface of neutrophils. The authors note that inhibitory effects of bacterially derived end target compounds on migration in response to intermediary chemoattractants may underlie important clinical complications, such as sepsis, that result, at least in part, from failure of neutrophil migration to the site of infection.
B. Heit, S. Tavener, E. Raharjo, P. Kubes, An intracellular signaling hierarchy determines direction of migration in opposing chemotactic gradients. J. Cell Biol. 159, 91-102 (2002). [Abstract] [Full Text]
Citation: How Neutrophils Heed the Call. Sci. STKE 2002, tw389 (2002).
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