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IL-3 Induces Down-Regulation of CCR3 Protein and mRNA in Human Eosinophils¹

Yasmin Dulkys^*, Christof Kluthe^*, Thomas Buschermöhle^*, Ines Barg^*, Sabine Knöß^*, Alexander Kapp^*, Amanda E. I. Proudfoot and Jörn Elsner²

^* Department of Dermatology and Allergology, Hannover Medical University, Hannover, Germany; and Serono Pharmaceutical Research Institute, Geneva, Switzerland

Cytokines and chemokines are responsible for the attraction and activation of eosinophils in allergic and inflammatory diseases. Whereas cytokines such as IL-3, IL-5, and GM-CSF activate eosinophils via heterodimeric receptors containing a distinct -chain (binding domain) and a common -chain (signaling domain), chemokines such as eotaxin activate eosinophils via seven-transmembrane G_i protein-coupled CCRs. Recent studies have demonstrated the importance of CCR3 on human eosinophils that undergo receptor recycling after chemokine activation, but the modulation of this receptor by cytokines has not yet been addressed. In this study, we demonstrate that IL-3 induces a dose- and time-dependent down-regulation of CCR3 from the surface of human eosinophils comparable to the CCR3-specific ligand eotaxin, whereas IL-5, GM-CSF, IL-4, IL-10, IL-13, IFN-, and TNF- had no effect. Maximal down-regulation of CCR3 in response to IL-3 was reached at 24 h. Reduction of CCR3 surface protein in response to IL-3 could be prevented by an anti-IL-3 mAb and was neither due to the release of CC chemokines nor to nonspecific binding of IL-3 to CCR3. Moreover, down-regulation was prevented by phenylarsine oxide, a nonspecific inhibitor of receptor internalization. After 24 h, IL-3-induced decrease of CCR3 surface expression correlated with diminished mRNA expression, suggesting a transcriptional regulation mechanism. Since wortmannin partially inhibited IL-3- but not eotaxin-induced CCR3 down-regulation, receptor down-modulation seems to underlie different signaling events. Therefore, these data suggest a novel role for the cytokine IL-3 in the activation process of eosinophils and its predominant chemokine receptor CCR3.

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