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Divisions of
* Gastroenterology and
Hematology/Oncology, Department of Internal Medicine, University of Michigan Medical Center and Department of Veterans Affairs Medical Center, Ann Arbor, MI 48109
In human neutrophils, IL-8 induces chemotaxis, the
respiratory burst, and granule release, and enhances cellular adhesion,
a 
2 integrin-dependent event. IL-8 stimulates neutrophil
adhesion to purified fibrinogen in a Mac-1-dependent manner.
Mitogen-activated protein kinase (MAPK) activation was detected in
human neutrophil lysates after treatment with IL-8 and PMA, but not the
activating mAb CBR LFA 1/2. IL-8-stimulated neutrophil adhesion to
fibrinogen was blocked 50% by the MAPK/extracellular signal-related
kinase-activating enzyme inhibitor PD098059. Adhesion was blocked
75% by inhibition of the phosphatidylinositol-3 kinase (PI3K)
pathway with LY294002, supporting that activation of both MAPK and PI3K
may play a role in IL-8-dependent inside-out signals that activate
Mac-1. Activation of MAPK was inhibited in IL-8-stimulated cells in the
presence of PI3K inhibitors LY294002 or wortmannin, supporting a model
in which PI3K is upstream of MAPK. IL-8-stimulated neutrophil adhesion
was inhibited 50% by bisindolylmaleimide-I, implicating protein kinase
C (PKC) in the intracellular signaling from the IL-8R to Mac-1. A
74-kDa molecular mass species was detected by an
activation-specific Ab to PKC when cells were stimulated with PMA or
IL-8, but not a 2-activating Ab. Inhibition of either
MAPK or PKC resulted in partial inhibition of IL-8-stimulated
polymorphonuclear neutrophil adhesion, and treatment with both
inhibitors simultaneously completely abolished IL-8-stimulated adhesion
to ligand. Inhibition of PI3K blocked MAPK activation, but not PKC
activation, suggesting a branch point that precedes PI3K activation.
These data suggest that both MAPK and PKC are activated in response to
IL-8 stimulation, and that these may represent independent pathways for
2 integrin activation in
neutrophils.
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