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and sIL-13R2 Suggest Opposite Effects on Allergic Responses1
,
* 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.
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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.
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