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Published online before print May 9, 2006

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.1105636

Received for publication November 7, 2005.

Accepted for publication March 21, 2006.

Article

IL-5-mediated eosinophil survival requires inhibition of GSK-3 and correlates with -catenin relocalization

Marcela Rosas ^*, Pascale Dijkers ^*, Caroline Lindemans ^*, Jan-Willem J. Lammers ^*, Leo Koenderman ^*, and Paul J. Coffer ^*@

*Department of Pulmonary Diseases and Molecular Immunology Lab, Department of Immunology, University Medical Center, Utrecht, The Netherlands

^@ To whom correspondence should be addressed. E-mail: p.j.coffer{at}umcutrecht.nl.

	Abstract

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 -chain and a -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. -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 -catenin in regulating eosinophil survival and suggests a novel mechanism by which IL-5 inhibits the constitutive apoptotic program in these cells.

Key Words: apoptosis • PI-3K

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