Differences in expression, affinity, and function of soluble (s)IL-4Rα and sIL-13Rα2 suggest opposite effects on allergic responses

IL-4 and IL-13 are each bound by soluble receptors (sRs) that block their activity. Both of these sRs (sIL-4R alpha and sIL-13R alpha 2) 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 alpha complexes rapidly dissociate, releasing active IL-4, whereas sIL13R alpha 2 and IL-13 form a stable complex that has a considerably longer half-life than uncomplexed IL-13, sIL-13R alpha 2, IL-4, or sIL-4R alpha. Approximately 25% of sIL-13R alpha 2 in serum is complexed to IL-13; this percentage and the absolute quantity of sIL13Ra2 in serum increase considerably during a Th2 response. sIL-13Ra2 gene expression is up-regulated by both IL-4 and IL-13; the effect of IL-4 is totally IL-4R alpha-dependent while the effect of IL-13 is partially IL-4R alpha-independent. Inhalation of an IL-13/sIL-13R alpha 2 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 alpha predominantly sustains, increases, and diffuses the effects of IL-4, whereas sIL-13Ra2 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.