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 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 (EC(50) approximately 2 microM) 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.
Kankaanranta
H
H
Thoracic Medicine, National Heart and Lung Institute, Imperial College of Science, Technology & Medicine, London, United Kingdom.
De Souza
P M
PM
Barnes
P J
PJ
Salmon
M
M
Giembycz
M A
MA
Lindsay
M A
MA
D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D002470:Cell Survival / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D016207:Cytokines / Q000502:physiology*; D003600:Cytosol / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004804:Eosinophils / Q000187:drug effects*; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D015848:Interleukin-5 / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases; D011725:Pyridines / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases
D016861:Cyclooxygenase Inhibitors; D016207:Cytokines; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D015848:Interleukin-5; D016859:Lipoxygenase Inhibitors; D011725:Pyridines; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one