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IL-4 Receptor Is an Important Modulator of IL-4 and IL-13 Receptor Binding: Implications for the Development of Therapeutic Targets¹

Allison-Lynn Andrews^2,*, John W. Holloway, Stephen T. Holgate^* and Donna E. Davies^*

^* The Brooke Laboratories, Division of Infection, Inflammation, and Repair, and Human Genetics Division, School of Medicine, Southampton General Hospital, Southampton, United Kingdom

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 with either the common -chain or the IL-13R chain 1 (IL-13R1). We found that IL-4 bound to the extracellular domain of IL-4R (soluble human (sh)IL-4R) with high affinity and specificity. In contrast with the sequential mechanism of binding and stabilization afforded by IL-4R to the binding of IL-13 to IL-13R1, neither common -chain nor IL-13R1 contributed significantly to the stabilization of the IL-4:IL-4R 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 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 only blocked IL-4. However, shIL-4R 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 plays a key role in the binding affinity of both IL-13R and IL-4R complexes. Under certain conditions, shIL-4R 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.

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