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Oxidation of the alarmin IL-33 regulates ST2-dependent inflammation..pdf (1.5 MB)

Oxidation of the alarmin IL-33 regulates ST2-dependent inflammation

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posted on 2016-03-16, 09:59 authored by E. S. Cohen, I. C. Scott, J. B. Majithiya, L. Rapley, B. P. Kemp, E. England, D. G. Rees, C. L. Overed-Sayer, J. Woods, N. J. Bond, C. S. Veyssier, K. J. Embrey, D. A. Sims, M. R. Snaith, K. A. Vousden, M. D. Strain, D. T. Chan, S. Carmen, C. E. Huntington, L. Flavell, J. Xu, B. Popovic, Christopher Edward Brightling, T. J. Vaughan, R. Butler, D. C. Lowe, D. R. Higazi, D. J. Corkill, R. D. May, M. A. Sleeman, T. Mustelin
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.

History

Citation

Nature Communications, 2015, 6 : 8327

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Infection, Immunity and Inflammation

Version

  • VoR (Version of Record)

Published in

Nature Communications

Publisher

Nature Publishing Group

eissn

2041-1723

Acceptance date

2015-08-11

Copyright date

2015

Available date

2016-03-16

Publisher version

http://www.nature.com/ncomms/2015/150914/ncomms9327/full/ncomms9327.html

Language

en

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