Inhibitors of PI 3-kinase and MEK kinase differentially affect mediator secretion from immunologically activated human basophils.
Effects of inhibitors of PI 3-kinase and MEK kinases were investigated on histamine, leukotriene C4(LTC4), and cytokine release from human basophils stimulated with anti-IgE. The PI 3-kinase antagonists wortmannin (> 10 nM) and LY 294002 (>1 microM) strongly inhibited anti-IgE-induced release of all mediators by 40-100%. This was contrasted by the effects of the MEK kinase inhibitor PD 098059, which weakly inhibited histamine, interleukin (IL)-4, and IL-13 release but was substantially more efficacious at blocking LTC4 production (>70% at 10 microM). Previous studies have shown that arachidonic acid synthesis is controlled by MEK kinases. We observed that wortmannin, LY 294002, and PD 098059 reduce basophil ERK-1,2 activation, thus implying that, with regard to arachidonic acid metabolism, MEK kinases are a downstream target for PI-3-kinase. Our results demonstrate a universal regulatory role played by PI 3-kinases in basophil mediator production and release, whereas MEK kinase signaling is largely limited to controlling arachidonic acid metabolism.
Gibbs
B F
BF
Department of Dermatology, Medical University of Lübeck, Germany.
Grabbe
J
J
D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology; D001491:Basophils / Q000276:immunology* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology; D006636:Histamine Release / Q000502:physiology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D018793:Interleukin-13 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D017997:Leukotriene C4 / Q000378:metabolism; D048728:MAP Kinase Kinase Kinase 1; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology
D000888:Antibodies, Anti-Idiotypic; D004791:Enzyme Inhibitors; D005419:Flavonoids; D018836:Inflammation Mediators; D018793:Interleukin-13; D015847:Interleukin-4; D017997:Leukotriene C4; D048728:MAP Kinase Kinase Kinase 1; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; C026408:anti-IgE antibodies; C482576:MAP3K1 protein, human; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one