The association of the cytoplasmic domains of interleukin 4 receptor alpha and interleukin 13 receptor alpha 2 regulates interleukin 4 signaling

Abstract

Interleukin-4 (IL-4) and Interleukin-13 (IL-13), key cytokines in the pathogenesis of allergic inflammatory disease, mediate their effects via a receptor composed of IL-13R?1 and IL-4R?. A third (decoy) receptor called IL-13R?2 regulates interleukin signaling through this receptor complex. We employed a variety of biophysical and cell-based techniques to decipher the role of this decoy receptor in mediating IL-4 signaling though the IL-4R?–IL-13R?1 receptor complex. Surface plasmon resonance (SPR) analysis showed that IL-13R?2 does not bind IL-4, and does not affect binding of IL-4 to IL-4R?. These results indicate that the extracellular domains of IL-4R? and IL-13R?2 are not involved in the regulation of IL-4 signaling by IL-13R?2. We next used a two-hybrid system to show that the cytoplasmic domains of IL-4R? and IL-13R?2 interact, and that the secondary structure of the IL-13R?2 intracellular domain is critical for this interaction. The cellular relevance of this interaction was next investigated. BEAS-2B bronchial epithelial cells that stably express full length IL-13R?2, or IL-13R?2 lacking its cytoplasmic domain, were established. Over expression of IL-13R?2 attenuated IL-4 and IL-13 mediated STAT6 phosphorylation. IL-13R?2 lacking its cytoplasmic domain continued to attenuate IL-13-mediated signaling, but had no effect on IL-4-mediated STAT6 signaling. Our results suggest that the physical interaction between the cytoplasmic domains of IL-13R?2 and IL-4R? regulates IL-4 signaling through the IL-4R?–IL-13R?1 receptor complex.

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Identifiers

ORCID for John W. Holloway: orcid.org/0000-0001-9998-0464

ORCID for Donna E. Davies: orcid.org/0000-0002-5117-2991

ORCID for Ali Tavassoli: orcid.org/0000-0002-7420-5063

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