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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 targets

IL-4 receptor ? is an important modulator of IL-4 and IL-13 receptor binding: implications for the development of therapeutic targets
IL-4 receptor ? 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? with either the common gamma-chain or the IL-13R chain ?1 (IL-13R?1). We found that IL-4 bound to the extracellular domain of IL-4Ralpha (soluble human (sh)IL-4R?) 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-13R?1, neither common gamma-chain nor IL-13R?1 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-4Ralpha 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.
0022-1767
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
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 ? is an important modulator of IL-4 and IL-13 receptor binding: implications for the development of therapeutic targets. Journal of Immunology, 176 (12), 7456-7461.

Record type: Article

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-4R? with either the common gamma-chain or the IL-13R chain ?1 (IL-13R?1). We found that IL-4 bound to the extracellular domain of IL-4Ralpha (soluble human (sh)IL-4R?) 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-13R?1, neither common gamma-chain nor IL-13R?1 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-4Ralpha 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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Published date: 15 June 2006

Identifiers

Local EPrints ID: 44317
URI: http://eprints.soton.ac.uk/id/eprint/44317
ISSN: 0022-1767
PURE UUID: c002a28c-fe2c-4d23-8998-81062895295a
ORCID for John W. Holloway: ORCID iD orcid.org/0000-0001-9998-0464
ORCID for Donna E. Davies: ORCID iD orcid.org/0000-0002-5117-2991

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Date deposited: 26 Feb 2007
Last modified: 25 Jul 2020 01:33

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