title: IL-4 receptor alpha is an important modulator of IL-4 and IL-13 receptor binding: implications for the development of therapeutic targets.
abstract: 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-4Ralpha with either the common gamma-chain or the IL-13R chain alpha1 (IL-13Ralpha1). We found that IL-4 bound to the extracellular domain of IL-4Ralpha (soluble human (sh)IL-4Ralpha) with high affinity and specificity. In contrast with the sequential mechanism of binding and stabilization afforded by IL-4Ralpha to the binding of IL-13 to IL-13Ralpha1, neither common gamma-chain nor IL-13Ralpha1 contributed significantly to the stabilization of the IL-4:IL-4Ralpha complex. Based on the different mechanisms of binding and stabilization of the IL-4R and IL-13R complexes, we compared the effects of shIL-4Ralpha 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-4Ralpha only blocked IL-4. However, shIL-4Ralpha 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-4Ralpha plays a key role in the binding affinity of both IL-13R and IL-4R complexes. Under certain conditions, shIL-4Ralpha 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.
authors.affiliation: The Brooke Laboratories, Division of Infection, Inflammation, and Repair, Southampton General Hospital, UK. ala@soton.ac.uk
authors.forename: Allison-Lynn
authors.initials: AL
authors.lastname: Andrews
authors.forename: John W
authors.initials: JW
authors.lastname: Holloway
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Holgate
authors.forename: Donna E
authors.initials: DE
authors.lastname: Davies
mesh_terms: D000276:Adjuvants, Immunologic / Q000502:physiology; D000328:Adult; D001665:Binding Sites; D002478:Cells, Cultured; D016503:Drug Delivery Systems / Q000379:methods; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit; D018793:Interleukin-13 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism / Q000502:physiology; D053661:Interleukin-13 Receptor alpha1 Subunit; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D053662:Interleukin-4 Receptor alpha Subunit; D007700:Kinetics; D008024:Ligands; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D021381:Protein Transport; D018123:Receptors, Interleukin / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D053660:Receptors, Interleukin-13; D019948:Receptors, Interleukin-4 / Q000819:agonists / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D050800:STAT6 Transcription Factor / Q000378:metabolism; D012995:Solubility; D020349:Surface Plasmon Resonance / Q000379:methods; D015854:Up-Regulation / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; C508181:IL13RA1 protein, human; C507941:IL2RG protein, human; C504000:IL4R protein, human; D053631:Interleukin Receptor Common gamma Subunit; D018793:Interleukin-13; D053661:Interleukin-13 Receptor alpha1 Subunit; D053662:Interleukin-4 Receptor alpha Subunit; D008024:Ligands; D018123:Receptors, Interleukin; D053660:Receptors, Interleukin-13; D019948:Receptors, Interleukin-4; D050800:STAT6 Transcription Factor; D015847:Interleukin-4