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Analysis of Signal Transduction Pathways in Human Eosinophils
Activated by Chemoattractants and the T-Helper 2-Derived Cytokines
Interleukin-4 and Interleukin-5
Paul J. Coffer,
René C. Schweizer,
Gerald R. Dubois,
Tjander Maikoe,
Jan-Willem J. Lammers, and
Leo Koenderman
From the Departments of Pulmonary Diseases and
Dermatology/Allergology, University Hospital Utrecht, Utrecht, The
Netherlands.
Activation and recruitment of eosinophils in allergic inflammation
is in part mediated by chemoattractants and T-helper 2 (Th2)-derived
cytokines. However, little is known concerning the signal transduction
mechanisms by which this activation occurs. We have investigated
tyrosine kinase-mediated activation of phosphatidylinositol 3-kinase
(PI3K) and compared this with the activation of the p21ras-ERK signaling pathway in human eosinophils. The related cytokines interleukin-3 (IL-3), IL-5, and granulocyte-macrophage
colony-stimulating factor (GM-CSF), all induced PI3K activity
detected in antiphosphotyrosine immunoprecipitates. Furthermore, the
chemoattractants platelet-activating factor (PAF),
RANTES, and C5a were also able to induce phosphotyrosine-associated PI3K activity. Protein kinase B (PKB) is a downstream target of PI3K
activation by growth factors. Induction of PKB phosphorylation in human
eosinophils was transiently induced on activation with the cytokines
IL-4 and IL-5, as well as the chemoattractants PAF, C5a, and RANTES
showing a broad activation profile. Surprisingly, analysis of the
activation of the mitogen-activated protein (MAP) kinases
p44ERK1 and p42ERK2, showed that ERK2, but not
ERK1, was transiently activated in human eosinophils after stimulation
with IL-5 or PAF. Activation kinetics correlated with activation of
p21ras by both cytokines and chemoattractants as measured by a novel
assay for guanosine triphosphate (GTP)-loading.
Finally, using specific inhibitors of both the p21ras-ERK and PI3K
signaling pathways, a role was demonstrated for PI3K, but not
p21ras-ERK, in activation of the serum-treated zymosan (STZ)-mediated
respiratory burst in IL-5 and PAF-primed eosinophils. In summary, these
data show that in human eosinophils, Th2-derived cytokines
differentially activate both PI3K and MAP kinase signal transduction
pathways with distinct functional consequences showing complex
regulation of eosinophil effector functions.
Blood, Vol. 91 No. 7 (April 1), 1998:
pp. 2547-2557
© 1998 by The American Society of Hematology.
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