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Differences in Expression, Affinity, and Function of Soluble (s)IL-4R and sIL-13R2 Suggest Opposite Effects on Allergic Responses¹

Marat Khodoun^*,, Christina Lewis, Jun-Qi Yang^*,, Tatyana Orekov^*,, Crystal Potter^*,, Thomas Wynn^¶, Margaret Mentink-Kane^¶, Gurjit K. Khurana Hershey, Marsha Wills-Karp and Fred D. Finkelman^2,*,,

^* Cincinnati Veterans Affairs Medical Center, Cincinnati, OH 45220; Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267; Division of Immunobiology and Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229; and ^¶ National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892

IL-4 and IL-13 are each bound by soluble receptors (sRs) that block their activity. Both of these sRs (sIL-4R and sIL-13R2) are present in low nanogram per milliliter concentrations in the serum from unstimulated mice, but differences in affinity and half-life suggest differences in function. Serum IL-4/sIL-4R complexes rapidly dissociate, releasing active IL-4, whereas sIL-13R2 and IL-13 form a stable complex that has a considerably longer half-life than uncomplexed IL-13, sIL-13R2, IL-4, or sIL-4R. Approximately 25% of sIL-13R2 in serum is complexed to IL-13; this percentage and the absolute quantity of sIL-13R2 in serum increase considerably during a Th2 response. sIL-13R2 gene expression is up-regulated by both IL-4 and IL-13; the effect of IL-4 is totally IL-4R-dependent while the effect of IL-13 is partially IL-4R-independent. Inhalation of an IL-13/sIL-13R2 complex does not affect the expression of IL-13-inducible genes but increases the expression of two genes, Vnn1 and Pira-1, whose products activate APCs and promote neutrophilic inflammation. These observations suggest that sIL-4R predominantly sustains, increases, and diffuses the effects of IL-4, whereas sIL-13R2 limits the direct effects of IL-13 to the site of IL-13 production and forms a stable complex with IL-13 that may modify the quality and intensity of an allergic inflammatory response.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a Merit Award (to F.D.F.) from the U.S. Department of Veterans Affairs, by National Institutes of Health grants to F.D.F. (R01 AI052099 and R01 AI55848) and G.K.H. (R01AI58157), and a National Institutes of Health P01 grant to M.W-K., G.K.K.H., and F.D.F. (HL076383).

² Address correspondence and reprint requests to Dr. Fred D. Finkelman, Cincinnati Veterans Authority, Medical Center, 3200 Vine Street, Cincinnati, OH 45220. E-mail address: ffinkelman{at}pol.net

³ Abbreviations used in this paper: s, soluble (prefix); GaKLH, goat antiserum to keyhole limpet hemocyanin; GaMD, goat anti-mouse IgD antiserum; i.t., intratracheal(ly); sR, soluble receptor.