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Diverging signal transduction pathways activated by interleukin-8 and
related chemokines in human neutrophils: interleukin-8, but not NAP-2 or
GRO alpha, stimulates phospholipase D activity
GP L'Heureux, S Bourgoin, N Jean, SR McColl and PH Naccache
Centre de Recherche en Rhumatologie et Immunologie, Centre de Recherche du
CHUL, Ste-Foy, Quebec, Canada.
Interleukin-8 (IL-8) and the structurally related cytokines neutrophil-
activating peptide-2 (NAP-2) and GRO alpha are powerful chemotactic agents
for human neutrophils. Although these three chemokines act by binding to
overlapping but not identical receptor subsets, the data available to date
have stressed the similarities in their mechanisms of action. The present
studies were undertaken to further our understanding of the signal
transduction mechanisms associated with these neutrophil agonists. IL-8,
NAP-2, and GRO alpha stimulated similar increases in the level of
cytoplasmic free calcium. They were also shown to stimulate qualitatively
similar increases in the levels of protein tyrosine phosphorylation. In
contrast, only IL-8 enhanced the formation of phosphatidylethanol (PEt),
the product catalyzed by phospholipase D (PLD) in the presence of ethanol.
The formation of PEt stimulated by IL-8 was inhibited by pertussis toxin
and the tyrosine kinase inhibitors erbstatin and herbimycin A. The ability
of IL-8 to stimulate the activity of PLD was additively enhanced, or
primed, by cytochalasin B and by tumor necrosis factor alpha. Although all
three chemokines increased the level of free cytoplasmic calcium to the
same extent, IL-8 was significantly more potent than either NAP-2 or GRO
alpha with respect to its ability to enhance CD11b expression and to
stimulate chemotactic and oxidative responses. The differences between
IL-8, NAP-2, and GRO alpha in their ability to stimulate PLD is likely to
be related to their respective binding affinities for the two IL-8
receptors (IL-8R-A and IL-8R-B). These results suggest that the signalling
pathways activated by IL-8R-A and IL-8R-B diverge at a step preceding the
activation of PLD.
Volume 85,
Issue 2,
pp. 522-531,
01/15/1995
Copyright © 1995 by The American Society of Hematology
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