IL-13Rα2 Reverses the Effects of IL-13 and IL-4 on Bronchial Reactivity and Acetylcholine-Induced Ca²⁺ Signaling

Abstract

Background: The interleukins IL-4 and IL-13 play a key role in the pathophysiology of asthma. The interleukin receptor IL-13Rα2 is believed to act as a decoy receptor, but until now, the functional significance of IL-13Rα2 remains vague. Methods: Bronchial reactivity was quantified in murine lung slices by digital video microscopy and acetylcholine (ACH)-induced Ca²⁺ signaling was measured in human airway smooth muscle cells (ASMC) using fluorescence microscopy. Results: IL-4 or IL-13 up to 50 ng/ml induced bronchial hyperreactivity. But after incubation with 100 ng/ml this effect was lost and bronchial responsiveness was again comparable to the control level. The effects of IL-4 and IL-13 on bronchial reactivity were paralleled by the effects on ASMC proliferation. Fifty nanograms per milliliter of IL-4 and IL-13 increased the Ca²⁺ response of human ASMC to ACH. At 100 ng/ml, however, the effects of the cytokines on the Ca²⁺ response were no longer evident. The expression of IL-13Rα2 increased with increasing concentrations of IL-4 or IL-13, reaching its maximum at 100 ng/ml. Blocking IL-13Rα2, the loss of the effect of IL-4 and IL-13 at 100 ng/ml on human ASMC proliferation and the ACH-induced Ca²⁺ response were no longer present. Conclusions: IL-4 and IL-13 induce bronchial hyperreactivity by changing the Ca²⁺ homeostasis of ASMC. These effects are counteracted by IL-13Rα2. The biological significance of IL-13Rα2 might be a protective function by regulating IL-13- and IL-4-mediated signal transduction and thereby limiting pathological alterations in Th2-mediated inflammatory diseases.

Mast Cell-Dependent Contraction of Human Airway Smooth Muscle Cell-Containing Collagen Gels: Influence of Cytokines, Matrix Metalloproteases, and Serine Proteases

“…Recent studies, however, suggest that IL-13R␣2 may mediate profibrotic responses to IL-13 by an undefined mechanism (35). Expression of IL-13R␣2 can be inducibly regulated on the surface of various cell types including smooth muscle cells (33). Human cell lines overexpressing IL-13R␣2 have reduced signaling responses to IL-13 (64,65), consistent with antagonist function, but there have been relatively few studies of IL-13R␣2 effects on IL-13 responses of primary human cells (33,66,67).…”

“…IL-13 responses are mediated through a receptor consisting of IL-13R␣1/IL-4R␣ chains. An additional binding chain, IL-13R␣2, is inducible on the surface of several cell types, including fibroblasts and smooth muscle cells, and antagonizes IL-13 responses on these cell types (33,34). Recently, however, it has been proposed that, under certain conditions, IL-13R␣2 may act as an agonist, rather than antagonist, of IL-13 responses (35).…”

IL-13Rα2 and IL-10 coordinately suppress airway inflammation, airway-hyperreactivity, and fibrosis in mice

“…IL-13Rα2, unlike the type 2 IL-4 receptor (IL-4Rα/IL-13Rα1), does not activate Stat6 signaling, but instead proportionally reduces IL-13 (17,18) and in some cases IL-4 activity (19). Although the function of IL-13 in allergic diseases has been studied extensively, IL-13Rα2 has received much less attention (20,21). IL-13Rα2 was recently shown to control bronchial reactivity following IL-13 stimulation in vitro (21).…”

“…Although the function of IL-13 in allergic diseases has been studied extensively, IL-13Rα2 has received much less attention (20,21). IL-13Rα2 was recently shown to control bronchial reactivity following IL-13 stimulation in vitro (21). Nevertheless, the role of the endogenous IL-13Rα2 has not to our knowledge been previously investigated in the lung.…”

IL-13 Antibodies Influence IL-13 Clearance in Humans by Modulating Scavenger Activity of IL-13Rα2

“…Described primarily as a decoy, IL-13Ra2 is a potent antagonist of IL-13 bioactivity mediated through the IL-13Ra1/IL-4Ra complex on human fibroblasts (5)(6)(7)(8), epithelial cells (9)(10)(11), keratinocytes (12,13), and smooth muscle cells (12,14,15). Recent reports suggested that IL-13Ra2 may have some signaling capacity, resulting in fibrotic responses to IL-13 (16).…”