title: IL-4-induced priming of human intestinal mast cells for enhanced survival and Th2 cytokine generation is reversible and associated with increased activity of ERK1/2 and c-Fos.
abstract: In synergy with stem cell factor (SCF), IL-4 strongly enhances mast cell proliferation and shifts IgE-dependent cytokine production in mature human mast cells toward an increased release of Th2 cytokines such as IL-3, IL-5, and IL-13 and a decreased IL-6 expression. In this study we analyzed the kinetics and the mechanisms of these IL-4 effects on mast cells purified from intestinal tissue. If the cells were first cultured with IL-4 for 14 days and then without IL-4 for another 14 days, mast cells lost the capacity of producing higher amounts of Th2 cytokines and regained the capacity of producing IL-6. The IL-4-induced up-regulation of mast cell proliferation and FcepsilonRI expression was also reversible if IL-4 was withdrawn for 14 days. Interestingly, in contrast to IL-4, proliferation and phenotype of human intestinal mast cells were not affected by IL-13 although both cytokines were capable of inducing STAT6 activation. Instead, IL-4 treatment (but not IL-13 treatment) was associated with an increased activity of ERK1/2 and c-Fos, the downstream target of ERK1/2 and component of the transcription factor AP-1. Consistently, mast cell proliferation and cytokine expression in response to IL-4 was blocked by the MEK inhibitor PD98059. In summary, our data show that the IL-4 effects on human intestinal mast cell functions are reversible and accompanied by an increased activity of ERK1/2 and c-Fos.
authors.affiliation: Department of Gastroenterology, Hepatology, and Endocrinology, Medical School of Hannover, Germany. lorentz.axel@mh-hannover.de
authors.forename: Axel
authors.initials: A
authors.lastname: Lorentz
authors.forename: Mikosch
authors.initials: M
authors.lastname: Wilke
authors.forename: Gernot
authors.initials: G
authors.lastname: Sellge
authors.forename: Hans
authors.initials: H
authors.lastname: Worthmann
authors.forename: Jürgen
authors.initials: J
authors.lastname: Klempnauer
authors.forename: Michael P
authors.initials: MP
authors.lastname: Manns
authors.forename: Stephan C
authors.initials: SC
authors.lastname: Bischoff
mesh_terms: D049109:Cell Proliferation; D002470:Cell Survival / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D016130:Immunophenotyping; D018793:Interleukin-13 / Q000502:physiology; D015847:Interleukin-4 / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000276:immunology; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis / Q000378:metabolism*; D017455:Receptors, IgE / Q000096:biosynthesis; D050800:STAT6 Transcription Factor; D019089:Stem Cell Factor / Q000494:pharmacology; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology
chemical_list: D016207:Cytokines; D005419:Flavonoids; D018793:Interleukin-13; D016760:Proto-Oncogene Proteins c-fos; D017455:Receptors, IgE; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D019089:Stem Cell Factor; D015534:Trans-Activators; D015847:Interleukin-4; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one