title: Late IL-3-induced phenotypic and functional alterations in human basophils require continuous IL-3 receptor signaling.
abstract: Cytokines of the GM-CSF family signal via the same receptor subunit (βc) and, thus, have overlapping effects on cells that express all cytokine-specific α-chains (IL-3Rα, IL-5Rα, GM-CSFRα), such as human basophils, whose rapid effector functions are similarly enhanced by IL-3, IL-5, and GM-CSF. However, previous work has shown that IL-3, but not IL-5 and GM-CSF, supports and induces allergy-associated functions of human basophils at later time points. This includes induction of Th2 cytokine and chemokine secretion, high-affinity IgE receptor-independent leukotriene C4 (LTC4) formation, expression of enzymes (e.g., RALDH2, granzyme B), and kinases (e.g., Pim1). Here, we address the question of why IL-3, but not IL-5 or GM-CSF, is capable of inducing these late responses in human basophils, and we investigate the mechanism that underlies the unique regulatory capacity of IL-3. We find that IL-3, IL-5, and GM-CSF rapidly activate the same canonical signaling cascades in a qualitatively identical manner with comparable strength, but we identify signaling duration as major discriminating factor. IL-5 and GM-CSF rapidly down-regulate surface levels of their receptors within minutes, concomitant with a rapid decay in signaling molecule activation and time-dependent loss of ability of these cytokines to prime basophils for functional responses. By contrast, IL-3 hardly down-regulates the α-chain of its receptor without depleting the common β-chain, which enables extraordinarily sustained signaling events, predominantly the activation of Stat5. Of interest, acute IL-3 signaling is not sufficient to induce persistent phenotypical and functional changes in human basophils. Induction of these functional late responses depends on continuous IL-3 receptor activation and signaling.
authors.affiliation: Institute of Immunology, University Hospital Bern, Inselspital, Switzerland.
authors.forename: Sacha S
authors.initials: SS
authors.lastname: Kämpfer
authors.affiliation: Institute of Immunology, University Hospital Bern, Inselspital, Switzerland.|University Institute of Clinical Chemistry, University Hospital Bern, Inselspital, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Odermatt
authors.affiliation: Institute of Immunology, University Hospital Bern, Inselspital, Switzerland.
authors.forename: Clemens A
authors.initials: CA
authors.lastname: Dahinden
authors.affiliation: Institute of Immunology, University Hospital Bern, Inselspital, Switzerland; michaela.fux@insel.ch.|University Institute of Clinical Chemistry, University Hospital Bern, Inselspital, Switzerland.
authors.forename: Michaela
authors.initials: M
authors.lastname: Fux
mesh_terms: D001491:Basophils / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D004804:Eosinophils / Q000187:drug effects / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D007377:Interleukin-3 / Q000378:metabolism*; D015848:Interleukin-5 / Q000378:metabolism; D007700:Kinetics; D008024:Ligands; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D016185:Receptors, Interleukin-3 / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D007377:Interleukin-3; D015848:Interleukin-5; D008024:Ligands; D016185:Receptors, Interleukin-3; D050799:STAT5 Transcription Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
keywords: GM-CSF cytokine family; human granulocytes; sustained cellular responses