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IL‐5‐mediated eosinophil survival requires inhibition of GSK‐3 and correlates with β‐catenin relocalization
Author(s) -
Rosas Marcela,
Dijkers Pascale F.,
Lindemans Caroline L.,
Lammers JanWillem J.,
Koenderman Leo,
Coffer Paul J.
Publication year - 2006
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.1105636
Subject(s) - biology , eosinophil , gsk 3 , microbiology and biotechnology , cytokine , interleukin 5 , signal transduction , cancer research , immunology , interleukin , asthma
Interleukin (IL)‐5 is a hematopoietic cytokine able to regulate differentiation, survival, and effector functions of eosinophils. It binds specifically to its receptor, which is composed of a cytokine‐specific α‐chain and a β‐chain shared with the receptors for IL‐3 and the granulocyte macrophage‐colony stimulating factor. The molecular mechanisms by which IL‐5 modulates eosinophil survival remain unclear. In this study, we demonstrate that IL‐5 withdrawal induces eosinophil apoptosis through a mitochondria‐dependent pathway, independently of Fas receptor activation. The lipid kinase phosphatidylinositol‐3 kinase plays a crucial role in the maintenance of eosinophil survival, as inhibition of its activity results in apoptosis. IL‐5 induces phosphorylation and thus, inhibition of the Forkhead transcription factor FOXO3a and glycogen synthase kinase 3 (GSK‐3). We analyzed expression of FOXO3a‐dependent transcriptional targets: Fas ligand or Bim (a proapoptotic Bcl‐2 family member), but neither was detected in apoptotic eosinophils. We further show that GSK‐3 is activated after IL‐5 withdrawal, and inhibition of its activity rescues eosinophils from apoptosis. β‐catenin, a direct GSK‐3 substrate, is present in the nucleus of IL‐5‐stimulated eosinophils, but it is translocated to the plasma membrane in the absence of cytokine in a GSK‐3‐dependent manner. This is the first report describing a potential role for GSK‐3 and β‐catenin in regulating eosinophil survival and suggests a novel mechanism by which IL‐5 inhibits the constitutive apoptotic program in these cells.