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

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Abstract
The interleukins IL-4 and IL-13 play a key role in the pathophysiology of asthma. The interleukin receptor IL-13Ralpha2 is believed to act as a decoy receptor, but until now, the functional significance of IL-13Ralpha2 remains vague. Bronchial reactivity was quantified in murine lung slices by digital video microscopy and acetylcholine (ACH)-induced Ca(2+) signaling was measured in human airway smooth muscle cells (ASMC) using fluorescence microscopy. 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 Ca(2+) response of human ASMC to ACH. At 100 ng/ml, however, the effects of the cytokines on the Ca(2+) response were no longer evident. The expression of IL-13Ralpha2 increased with increasing concentrations of IL-4 or IL-13, reaching its maximum at 100 ng/ml. Blocking IL-13Ralpha2, the loss of the effect of IL-4 and IL-13 at 100 ng/ml on human ASMC proliferation and the ACH-induced Ca(2+) response were no longer present. IL-4 and IL-13 induce bronchial hyperreactivity by changing the Ca(2+) homeostasis of ASMC. These effects are counteracted by IL-13Ralpha2. The biological significance of IL-13Ralpha2 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.