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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.

journal_name

J Leukoc Biol

journal_title

Journal of leukocyte biology

authors

Kämpfer SS,Odermatt A,Dahinden CA,Fux M

doi

10.1189/jlb.2A0715-292RR

subject

Has Abstract

pub_date

2017-01-01 00:00:00

pages

227-238

issue

eissn

0741-5400

issn

1938-3673

pii

jlb.2A0715-292RR

journal_volume

101

pub_type

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Late IL-3-induced phenotypic and functional alterations in human basophils require continuous IL-3 receptor signaling.