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Blood, 15 September 2000, Vol. 96, No. 6, pp. 2199-2205
IMMUNOBIOLOGY
Phosphatidylinositol-3 kinase regulates p21ras
activation during IgE-mediated stimulation of
human basophils
Katsushi Miura and
Donald
W. MacGlashan Jr
From the Johns Hopkins Asthma and Allergy Center,
Baltimore, MD.
Cross-linking of IgE or a bacterial product (f-Met-Leu-Phe;
FMLP) induces the release of leukotriene C4 (LTC4) and histamine in
human basophils. However, the signaling mechanisms in human basophils
are only partially understood. It has been demonstrated that
extracellular signal-regulated kinases (ERK1/2) specifically regulate
the pathway for LTC4 generation, but not for histamine release and
interleukin-4 production. More recent studies have suggested that
tyrosine kinase (syk)-mediated phosphorylation of shc is responsible
for the ras-ERK cascade via the formation of shc-Grb2-Sos2 following
stimulation with anti-IgE antibody, but not FMLP, in human basophils.
However, while characterizing the role of phosphatidylinositol (PI)-3
kinase in signaling pathways leading to basophil mediator release, it
was noted that this pathway might also regulate p21ras activation.
Anti-IgE antibody, but not FMLP, resulted in phosphorylation of p85
(regulatory subunit of PI3 kinase), suggesting activation of PI3
kinase. Inhibition of PI3 kinase by selective inhibitor (LY294002)
abolished anti-IgE antibody- but not FMLP-induced phosphorylation of
MEK1 (MAPK kinase/ERK kinase) and ERKs while inhibiting LTC4 generation
as well as histamine release. IgE-mediated activation of ras (upstream
of MEK-ERK) was also inhibited. But, further upstream, phosphorylation
of syk and of shc and inducible association between shc and Grb2 were
not affected. Furthermore, the IgE-mediated cytosolic calcium response
([Ca++]i) was also diminished. These results
suggest that functional responses may be dependent on the activity of
PI3 kinase, which regulates at least 2 important signaling pathways: by
regulating activation of ras for the MEK-ERK pathway and the increase
in [Ca++]i.
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