The Journal of Experimental Medicine
Avanti Polar Lipids, Inc.
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Published online October 13, 2008
doi:10.1084/jem.20080452
The Journal of Experimental Medicine, Vol. 205, No. 11, 2595-2608
The Rockefeller University Press, 0022-1007 $30.00
© 2008 Junttila et al.
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ARTICLE

 Tuning sensitivity to IL-4 and IL-13: differential expression of IL-4R{alpha}, IL-13R{alpha}1, and {gamma}c regulates relative cytokine sensitivity

Ilkka S. Junttila1, Kiyoshi Mizukami1, Harold Dickensheets2, Martin Meier-Schellersheim1, Hidehiro Yamane1, Raymond P. Donnelly2, and William E. Paul1

1 Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
2 Division of Therapeutic Proteins, Center for Drug Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892

CORRESPONDENCE Ilkka S. Junttila: junttilai{at}niaid.nih.gov

Interleukin (IL)-4 and -13 are related cytokines sharing functional receptors. IL-4 signals through the type I (IL-4R{alpha}/common {gamma}-chain [{gamma}c]) and the type II (IL-4R{alpha}/-13R{alpha}1) IL-4 receptors, whereas IL-13 utilizes only the type II receptor. In this study, we show that mouse bone marrow–derived macrophages and human and mouse monocytes showed a much greater sensitivity to IL-4 than to IL-13. Lack of functional {gamma}c made these cells poorly responsive to IL-4, while retaining full responsiveness to IL-13. In mouse peritoneal macrophages, IL-4 potency exceeds that of IL-13, but lack of {gamma}c had only a modest effect on IL-4 signaling. In contrast, IL-13 stimulated greater responses than IL-4 in fibroblasts. Using levels of receptor chain expression and known binding affinities, we modeled the assemblage of functional type I and II receptor complexes. The differential expression of IL-4R{alpha}, IL-13R{alpha}1, and {gamma}c accounted for the distinct IL-4–IL-13 sensitivities of the various cell types. These findings provide an explanation for IL-13's principal function as an "effector" cytokine and IL-4's principal role as an "immunoregulatory" cytokine.

Abbreviations used: Arg, Arginase; BMDM, BM-derived macrophage; EMSA, electrophoretic mobility shift assay; {gamma}c, IL-2 receptor-{gamma} chain; IRS, insulin receptor substrate; MFI, median fluorescence intensity; PM, peritoneal macrophage; Tg, thioglycollate; TLR, Toll-like receptor.


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