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SB 203580, an Inhibitor of p38 Mitogen-Activated Protein Kinase, Enhances Constitutive Apoptosis of Cytokine-Deprived Human Eosinophils
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 a...
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Published in: | The Journal of pharmacology and experimental therapeutics 1999-08, Vol.290 (2), p.621 |
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Main Authors: | , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Online Access: | Get full text |
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Summary: | 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 âfastâ- or âslowâ-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 (EC 50 â¼2 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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ISSN: | 0022-3565 1521-0103 |