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PNAS 103 (9): 3333-3338

Copyright © 2006 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / IMMUNOLOGY

Cytokine receptor-mediated trafficking of preformed IL-4 in eosinophils identifies an innate immune mechanism of cytokine secretion

Lisa A. Spencer*,{dagger}, Rossana C. N. Melo*,{dagger},{ddagger}, Sandra A. C. Perez*,§, Staci P. Bafford*, Ann M. Dvorak, and Peter F. Weller*,||

Departments of *Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215; {ddagger}Department of Biology, Federal University of Juiz de Fora, CEP 36036-330, Juiz de Fora, MG, Brazil; and §Laboratory of Inflammation and Department of Physiology and Pharmacodynamics, Oswaldo Cruz Institute, Fiocruz, CEP 21045-900, Rio de Janeiro, Brazil

Edited by Seymour J. Klebanoff, University of Washington School of Medicine, Seattle, WA, and approved January 6, 2006

Received for publication October 17, 2005.

Abstract: Although leukocytes of the innate immune system, including eosinophils, contain within their granules preformed stores of cytokines available for selective and rapid release, little is known about the mechanisms governing the mobilization and secretion of these cytokines. Here we show that a cytokine receptor, the IL-4 receptor {alpha} chain, mediates eotaxin-stimulated mobilization of preformed IL-4 from eosinophil granules into secretory vesicles. Eosinophils contain substantial intracellular quantities of several granule- and vesicle-associated cytokine receptors, including IL-4, IL-6, and IL-13 receptors as well as CCR3. Both IL-4 and IL-4 receptor {alpha} chain colocalized in eosinophil granules; and after eotaxin-stimulation, IL-4 receptor {alpha} chain, bearing bound IL-4, was mobilized into secretory vesicles. These findings indicate that intracellular cytokine receptors within secretory vesicles transport their cognate cytokines requisite for the secretion of cytokines preformed in innate immune leukocytes.

Key Words: intracellular cytokine receptor • intracellular cytokine trafficking • piecemeal degranulation • vesicular transport

{dagger}L.A.S. and R.C.N.M. contributed equally to this work.

Author contributions: L.A.S., R.C.N.M., and P.F.W. designed research; L.A.S., R.C.N.M., S.A.C.P., and S.P.B. performed research; L.A.S., R.C.N.M., S.A.C.P., A.M.D., and P.F.W. analyzed data; and L.A.S., R.C.N.M., and P.F.W. wrote the paper.

Conflict of interest statement: No conflicts declared.

This paper was submitted directly (Track II) to the PNAS office.

||To whom correspondence should be addressed at: Beth Israel Deaconess Medical Center, 330 Brookline Avenue, DA-617, Boston, MA 02215. E-mail: pweller{at}bidmc.harvard.edu

© 2006 by The National Academy of Sciences of the USA

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