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Title: Oxidation of the alarmin IL-33 regulates ST2-dependent inflammation
Authors: Cohen, E. S.
Scott, I. C.
Majithiya, J. B.
Rapley, L.
Kemp, B. P.
England, E.
Rees, D. G.
Overed-Sayer, C. L.
Woods, J.
Bond, N. J.
Veyssier, C. S.
Embrey, K. J.
Sims, D. A.
Snaith, M. R.
Vousden, K. A.
Strain, M. D.
Chan, D. T.
Carmen, S.
Huntington, C. E.
Flavell, L.
Xu, J.
Popovic, B.
Brightling, Christopher Edward
Vaughan, T. J.
Butler, R.
Lowe, D. C.
Higazi, D. R.
Corkill, D. J.
May, R. D.
Sleeman, M. A.
Mustelin, T.
First Published: 14-Sep-2015
Publisher: Nature Publishing Group
Citation: Nature Communications, 2015, 6 : 8327
Abstract: In response to infections and irritants, the respiratory epithelium releases the alarmin interleukin (IL)-33 to elicit a rapid immune response. However, little is known about the regulation of IL-33 following its release. Here we report that the biological activity of IL-33 at its receptor ST2 is rapidly terminated in the extracellular environment by the formation of two disulphide bridges, resulting in an extensive conformational change that disrupts the ST2 binding site. Both reduced (active) and disulphide bonded (inactive) forms of IL-33 can be detected in lung lavage samples from mice challenged with Alternaria extract and in sputum from patients with moderate-severe asthma. We propose that this mechanism for the rapid inactivation of secreted IL-33 constitutes a 'molecular clock' that limits the range and duration of ST2-dependent immunological responses to airway stimuli. Other IL-1 family members are also susceptible to cysteine oxidation changes that could regulate their activity and systemic exposure through a similar mechanism.
DOI Link: 10.1038/ncomms9327
eISSN: 2041-1723
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © 2015, Macmillan Publishers Limited. All rights reserved. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit
Appears in Collections:Published Articles, Dept. of Infection, Immunity and Inflammation

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