IL-4 receptor α is an important modulator of IL-4 and IL-13 receptor binding:: Implications for the development of therapeutic targets

IL-4 is a key cytokine associated with allergy and asthma. Induction of cell signaling by IL-4 involves interaction with its cognate receptors, a complex of IL-4R alpha with either the common gamma-chain or the IL-13R chain alpha 1 (IL-13R alpha 1). We found that IL-4 bound to the extracellular domain of IL-4R alpha (soluble human (sh)IL-4R alpha) with high affinity and specificity. In contrast with the sequential mechanism of binding and stabilization afforded by IL-4R alpha to the binding of IL-13 to IL-13R alpha 1, neither common gamma-chain nor IL-13R alpha 1 contributed significantly to the stabilization of the IL-4:IL-4Ra complex. Based on the different mechanisms of binding and stabilization of the IL-4R and IL-13R complexes, we compared the effects of shIL-4R alpha and an IL-4 double mutein (R121D/Y124D, IL-4R antagonist) on IL-4- and IL-13-mediated responses. Whereas IL-4R antagonist blocked responses to both cytokines, shIL-4R alpha only blocked IL-4. However, shIL-4Ra stabilized and augmented IL-13.-mediated STAT6 activation and eotaxin production by primary human bronchial fibroblasts at suboptimal doses of IL-13. These data demonstrate that IL-4R alpha plays a key role in the binding affinity of both IL-13R and IL-4R complexes. Under certain conditions, shIL-4Ra has the potential to stabilize binding IL-13 to its receptor to augment IL-13-mediated responses. Thus, complete understanding of the binding interactions between IL-4 and IL-13 and their cognate receptors may facilitate development of novel treatments for asthma that selectively target these cytokines without unpredicted or detrimental side effects.