IL-4 receptor alpha is an important modulator of IL-4 and IL-13 receptor binding: implications for the development of therapeutic targets
IL-4 receptor alpha 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-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.
Adjuvants, Immunologic, Adult, Binding Sites, Cells, Cultured, Drug Delivery Systems, Female, Fibroblasts, Humans, Interleukin Receptor Common gamma Subunit, Interleukin-13, Interleukin-13 Receptor alpha1 Subunit, Interleukin-4, Interleukin-4 Receptor alpha Subunit, Kinetics, Ligands, Male, Middle Aged, Phosphorylation, Protein Transport, Receptors, Interleukin, Receptors, Interleukin-13, Receptors, Interleukin-4, STAT6 Transcription Factor, Solubility, Surface Plasmon Resonance, Up-Regulation, Comparative Study, Journal Article, Research Support, Non-U.S. Gov't
7456-7461
Andrews, Allison-Lynn
4ddaec43-0f43-40cd-a191-aa53b0b30f16
Holloway, John W.
4bbd77e6-c095-445d-a36b-a50a72f6fe1a
Holgate, Stephen T.
2e7c17a9-6796-436e-8772-1fe6d2ac5edc
Davies, Donna E.
7de8fdc7-3640-4e3a-aa91-d0e03f990c38
15 June 2006
Andrews, Allison-Lynn
4ddaec43-0f43-40cd-a191-aa53b0b30f16
Holloway, John W.
4bbd77e6-c095-445d-a36b-a50a72f6fe1a
Holgate, Stephen T.
2e7c17a9-6796-436e-8772-1fe6d2ac5edc
Davies, Donna E.
7de8fdc7-3640-4e3a-aa91-d0e03f990c38
Andrews, Allison-Lynn, Holloway, John W., Holgate, Stephen T. and Davies, Donna E.
(2006)
IL-4 receptor alpha is an important modulator of IL-4 and IL-13 receptor binding: implications for the development of therapeutic targets.
Journal of Immunology, 176 (12), .
(doi:10.4049/jimmunol.176.12.7456).
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.
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Published date: 15 June 2006
Keywords:
Adjuvants, Immunologic, Adult, Binding Sites, Cells, Cultured, Drug Delivery Systems, Female, Fibroblasts, Humans, Interleukin Receptor Common gamma Subunit, Interleukin-13, Interleukin-13 Receptor alpha1 Subunit, Interleukin-4, Interleukin-4 Receptor alpha Subunit, Kinetics, Ligands, Male, Middle Aged, Phosphorylation, Protein Transport, Receptors, Interleukin, Receptors, Interleukin-13, Receptors, Interleukin-4, STAT6 Transcription Factor, Solubility, Surface Plasmon Resonance, Up-Regulation, Comparative Study, Journal Article, Research Support, Non-U.S. Gov't
Identifiers
Local EPrints ID: 44317
URI: http://eprints.soton.ac.uk/id/eprint/44317
ISSN: 0022-1767
PURE UUID: c002a28c-fe2c-4d23-8998-81062895295a
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Date deposited: 26 Feb 2007
Last modified: 16 Mar 2024 02:57
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Author:
Allison-Lynn Andrews
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