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Vol. 290, Issue 2, 621-628, August 1999
Thoracic Medicine, National Heart and Lung Institute, Imperial
College of Science, Technology & Medicine, London, United Kingdom
The role of p38 mitogen-activated protein (MAP) kinase, and
extracellular-regulated protein kinase -1 and -2 in regulating constitutive apoptosis and interleukin (IL)-5-induced survival of human
eosinophils have been investigated. Two populations of donors were
identified whose eosinophils, in the absence of exogenous cytokines,
underwent apoptosis at different rates. Eosinophils were thus
arbitrarily classified as either "fast"- or "slow"-dying cells,
where greater or less than 15% of the cells were apoptotic at 2 days,
respectively. The selective p38 MAP kinase inhibitor, SB 203580, increased constitutive eosinophil apoptosis in both populations
(EC50 ~2 µM) as evinced from morphological
analysis, flow cytometry, and DNA laddering. The ability of SB 203580 to kill eosinophils was not due to nonspecific toxicity or through the
inhibition of prostanoid or leukotriene production. Exposure of
eosinophils to IL-5, at a concentration (10 pM) that enhanced survival
maximally, abolished SB 203580-induced apoptosis. In contrast PD
098059, which selectively blocks MAP kinase kinase (MEK) 1, did not
affect apoptosis of fast- or slow-dying eosinophils, or the enhanced
survival of cells effected by IL-5. Collectively, these results suggest
that: 1) the basal activity of p38 MAP kinase may regulate the survival
of cytokine-deprived eosinophils through inhibition of apoptosis, 2)
the enhancement of eosinophil survival effected by IL-5 is mediated by
a mechanism(s) divorced from the activation of p38 MAP kinase, and 3)
neither spontaneous eosinophil apoptosis nor their enhanced survival by
IL-5 involves the activation of MEK-1.
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