title: Akt cross-links IL-4 priming, stem cell factor signaling, and IgE-dependent activation in mature human mast cells.
abstract: Challenge of human mast cells with both stem cell factor (SCF) and IL-4 enhances antigen-dependent mediator release raising the assumption of intracellular crosstalk between the IL-4, SCF, and FcɛRI signaling pathways. Here, we analyzed the intracellular crosstalk of IL-4-, SCF-, and IgE-dependent activation pathways in mucosal mast cells isolated from human intestine. The release of β-hexosaminidase, leukotriene C(4), and IL-8, but not IL-6, was strongly enhanced in response to sequential challenge of mast cells with IL-4, SCF and FcɛRI cross-linking compared to stimulation by FcɛRI cross-linking alone. Previous studies revealed that MAPK and other serine/threonine kinases are involved in mast cell activation processes. Here we found that activation of mast cells by FcɛRI cross-linking alone results in phosphorylation of ERK and p38, but not of Akt. Stimulation with SCF alone also induced phosphorylation of ERK and p38, and additionally of Akt. IL-4 priming enhanced activation of ERK, but blocked activation of p38. Activation of p38 was required for IL-6 production explaining the inhibitory effect of IL-4 on IL-6 expression in human mast cells. Moreover, IL-4 priming that anteceded FcɛRI cross-linking induced activation of Akt. The combined challenge of mast cells with IL-4, SCF and FcɛRI cross-linking substantially up-regulated activation of Akt, whereas blocking of Akt inhibited the pronounced production and release of IL-8 in response to the three mast cell agonists. In summary, our data demonstrate that ERK, p38, and especially Akt play an important role in cross-linking IL-4 priming, SCF signaling, and IgE-dependent activation of mature human mast cells.
authors.affiliation: Department of Nutritional Medicine, University of Hohenheim, Fruwirthstraße 12, 70593 Stuttgart, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Feuser
authors.forename: Katharina
authors.initials: K
authors.lastname: Feilhauer
authors.forename: Ludger
authors.initials: L
authors.lastname: Staib
authors.forename: Stephan C
authors.initials: SC
authors.lastname: Bischoff
authors.forename: Axel
authors.initials: A
authors.lastname: Lorentz
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects; D003432:Cross-Linking Reagents / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D007073:Immunoglobulin E / Q000276:immunology*; D018836:Inflammation Mediators / Q000378:metabolism; D015847:Interleukin-4 / Q000276:immunology*; D015850:Interleukin-6 / Q000276:immunology; D008407:Mast Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017455:Receptors, IgE / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D019089:Stem Cell Factor / Q000276:immunology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D003432:Cross-Linking Reagents; D018836:Inflammation Mediators; D015850:Interleukin-6; D047428:Protein Kinase Inhibitors; D017455:Receptors, IgE; D019089:Stem Cell Factor; D015847:Interleukin-4; D007073:Immunoglobulin E; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases