Regulation of mediator secretion in human basophils by p38 mitogen-activated protein kinase: phosphorylation is sensitive to the effects of phosphatidylinositol 3-kinase inhibitors and calcium mobilization.
Although human basophils modulate allergic diseases by secreting histamine, leukotriene C(4), interleukin (IL)-4, and IL-13, the intermediary signals controlling the release of these mediators are poorly understood. Here, we show that p38 mitogen-activated protein kinase (MAPK) crucially affects basophil activation following stimulation with various secretagogues. Phosphorylation of p38 MAPK occurred within 5 min following anti-immunoglobulin (Ig)E stimulation, but was more rapidly activated in basophils stimulated with formyl-Met-Leu-Phe or A23187. Additionally, activation of p38 MAPK to the above stimuli was dependent on extracellular influx and intracellular mobilization of calcium. SB 203580, a specific p38 MAPK inhibitor, blocked anti-IgE-induced secretion of all basophil mediators and reduced not only p38 MAPK, but also extracellular signal-regulated kinases 1 and 2 activity, whereas the MAPK antagonist, PD 098059, did not affect p38 MAPK. IgE-dependent activation of p38 MAPK and MKK3/6 was affected by LY 294002 and wortmannin, suggesting that these kinases are targets for phosphatidylinositol 3 kinase (PI 3-K). We conclude that p38 MAPK is a pivotal regulator of basophil function downstream of PI 3-K activation and calcium mobilization.
Gibbs
Bernhard F
BF
Department of Dermatology, Medical University of Lübeck, Germany. bfgibbs@gmx.de
Plath
Katharina E S
KE
Wolff
Helmut H
HH
Grabbe
Jürgen
J
D000420:Albuterol / Q000031:analogs & derivatives* / Q000494:pharmacology; D001491:Basophils / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism; D000001:Calcimycin / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology; D006636:Histamine Release / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007073:Immunoglobulin E / Q000276:immunology; D018793:Interleukin-13 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism*; D017997:Leukotriene C4 / Q000378:metabolism*; D048371:MAP Kinase Kinase 3; D048669:MAP Kinase Kinase 6; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D009025:Morpholines / Q000494:pharmacology; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D000068299:Salmeterol Xinafoate; D015290:Second Messenger Systems / Q000187:drug effects; D013806:Theophylline / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
D000420:Albuterol; D000001:Calcimycin; D002121:Calcium Channel Blockers; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002867:Chromones; D000242:Cyclic AMP; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D007073:Immunoglobulin E; D018793:Interleukin-13; D015847:Interleukin-4; D007378:Interleukins; D017997:Leukotriene C4; D048371:MAP Kinase Kinase 3; D048669:MAP Kinase Kinase 6; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D009025:Morpholines; D009240:N-Formylmethionine Leucyl-Phenylalanine; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D011725:Pyridines; D000068299:Salmeterol Xinafoate; D013806:Theophylline; D048051:p38 Mitogen-Activated Protein Kinases; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C482530:MAP2K3 protein, human; C482566:MAP2K6 protein, human; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one