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Identification of small‐molecule elastase inhibitors as antagonists of IL‐36 cytokine activation
IL‐1 family cytokines act as apical initiators of inflammation in many settings and can promote the production of a battery of inflammatory cytokines, chemokines and other inflammatory mediators in diverse cell types. IL‐36α, IL‐36β and IL‐36γ, which belong to the extended IL‐1 family, have been imp...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5929933/ https://www.ncbi.nlm.nih.gov/pubmed/29744290 http://dx.doi.org/10.1002/2211-5463.12406 |
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author | Sullivan, Graeme P. Davidovich, Pavel B. Sura‐Trueba, Sylvia Belotcerkovskaya, Ekaterina Henry, Conor M. Clancy, Danielle M. Zinoveva, Anna Mametnabiev, Tazhir Garabadzhiu, Alexander V. Martin, Seamus J. |
author_facet | Sullivan, Graeme P. Davidovich, Pavel B. Sura‐Trueba, Sylvia Belotcerkovskaya, Ekaterina Henry, Conor M. Clancy, Danielle M. Zinoveva, Anna Mametnabiev, Tazhir Garabadzhiu, Alexander V. Martin, Seamus J. |
author_sort | Sullivan, Graeme P. |
collection | PubMed |
description | IL‐1 family cytokines act as apical initiators of inflammation in many settings and can promote the production of a battery of inflammatory cytokines, chemokines and other inflammatory mediators in diverse cell types. IL‐36α, IL‐36β and IL‐36γ, which belong to the extended IL‐1 family, have been implicated as key initiators of skin inflammation in psoriasis. IL‐36γ is highly upregulated in lesional skin from psoriatic individuals, and heritable mutations in the natural IL‐36 receptor antagonist result in a severe form of psoriasis. IL‐36 family cytokines are initially expressed as inactive precursors that require proteolytic processing for activation. The neutrophil granule‐derived protease elastase proteolytically processes and activates IL‐36α and IL‐36γ, increasing their biological activity ~ 500‐fold, and also robustly activates IL‐1α and IL‐33 through limited proteolytic processing. Consequently, inhibitors of elastase activity may have potential as anti‐inflammatory agents through antagonizing the activation of multiple IL‐1 family cytokines. Using in silico screening approaches, we have identified small‐molecule inhibitors of elastase that can antagonize activation of IL‐36γ by the latter protease. The compounds reported herein may have utility as lead compounds for the development of inhibitors of elastase‐mediated activation of IL‐36 and other IL‐1 family cytokines in inflammatory conditions, such as psoriasis. |
format | Online Article Text |
id | pubmed-5929933 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-59299332018-05-09 Identification of small‐molecule elastase inhibitors as antagonists of IL‐36 cytokine activation Sullivan, Graeme P. Davidovich, Pavel B. Sura‐Trueba, Sylvia Belotcerkovskaya, Ekaterina Henry, Conor M. Clancy, Danielle M. Zinoveva, Anna Mametnabiev, Tazhir Garabadzhiu, Alexander V. Martin, Seamus J. FEBS Open Bio Research Articles IL‐1 family cytokines act as apical initiators of inflammation in many settings and can promote the production of a battery of inflammatory cytokines, chemokines and other inflammatory mediators in diverse cell types. IL‐36α, IL‐36β and IL‐36γ, which belong to the extended IL‐1 family, have been implicated as key initiators of skin inflammation in psoriasis. IL‐36γ is highly upregulated in lesional skin from psoriatic individuals, and heritable mutations in the natural IL‐36 receptor antagonist result in a severe form of psoriasis. IL‐36 family cytokines are initially expressed as inactive precursors that require proteolytic processing for activation. The neutrophil granule‐derived protease elastase proteolytically processes and activates IL‐36α and IL‐36γ, increasing their biological activity ~ 500‐fold, and also robustly activates IL‐1α and IL‐33 through limited proteolytic processing. Consequently, inhibitors of elastase activity may have potential as anti‐inflammatory agents through antagonizing the activation of multiple IL‐1 family cytokines. Using in silico screening approaches, we have identified small‐molecule inhibitors of elastase that can antagonize activation of IL‐36γ by the latter protease. The compounds reported herein may have utility as lead compounds for the development of inhibitors of elastase‐mediated activation of IL‐36 and other IL‐1 family cytokines in inflammatory conditions, such as psoriasis. John Wiley and Sons Inc. 2018-03-25 /pmc/articles/PMC5929933/ /pubmed/29744290 http://dx.doi.org/10.1002/2211-5463.12406 Text en © 2018 The Authors. Published by FEBS Press and John Wiley & Sons Ltd. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Articles Sullivan, Graeme P. Davidovich, Pavel B. Sura‐Trueba, Sylvia Belotcerkovskaya, Ekaterina Henry, Conor M. Clancy, Danielle M. Zinoveva, Anna Mametnabiev, Tazhir Garabadzhiu, Alexander V. Martin, Seamus J. Identification of small‐molecule elastase inhibitors as antagonists of IL‐36 cytokine activation |
title | Identification of small‐molecule elastase inhibitors as antagonists of IL‐36 cytokine activation |
title_full | Identification of small‐molecule elastase inhibitors as antagonists of IL‐36 cytokine activation |
title_fullStr | Identification of small‐molecule elastase inhibitors as antagonists of IL‐36 cytokine activation |
title_full_unstemmed | Identification of small‐molecule elastase inhibitors as antagonists of IL‐36 cytokine activation |
title_short | Identification of small‐molecule elastase inhibitors as antagonists of IL‐36 cytokine activation |
title_sort | identification of small‐molecule elastase inhibitors as antagonists of il‐36 cytokine activation |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5929933/ https://www.ncbi.nlm.nih.gov/pubmed/29744290 http://dx.doi.org/10.1002/2211-5463.12406 |
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