Akt cross-links IL-4 priming, stem cell factor signaling, and IgE-dependent activation in mature human mast cells

• Published in: Molecular immunology 2011-01, Vol.48 (4), p.546-552
• Main Authors: Feuser, Katrin, Feilhauer, Katharina, Staib, Ludger, Bischoff, Stephan C., Lorentz, Axel
• Format: Article
• Language: English
• Subjects: Cell Differentiation - drug effects; Cross-Linking Reagents - metabolism; crosslinking; Cytokines; enzyme activation; Enzyme Activation - drug effects; Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors; Extracellular Signal-Regulated MAP Kinases - metabolism; Human; Humans; immunoglobulin E; Immunoglobulin E - immunology; immunologic receptors; Inflammation Mediators - metabolism; interleukin-4; Interleukin-4 - immunology; interleukin-6; Interleukin-6 - immunology; interleukin-8; intestinal mucosa; Mast cell; mast cells; Mast Cells - cytology; Mast Cells - drug effects; Mast Cells - enzymology; Mast Cells - immunology; mitogen-activated protein kinase; Mucosa; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; p38 Mitogen-Activated Protein Kinases - metabolism; Phosphorylation - drug effects; Protein Kinase Inhibitors - pharmacology; protein phosphorylation; Proto-Oncogene Proteins c-akt - metabolism; Receptors, IgE - immunology; Signal transduction; Signal Transduction - drug effects; Signal Transduction - immunology; stem cell factor; Stem Cell Factor - immunology
• ISSN: 0161-5890; 1872-9142
• DOI: 10.1016/j.molimm.2010.10.010

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 C4, 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.