Ainscough, JS, Macleod, T, McGonagle, D et al. (5 more authors) (2017) Cathepsin S is the major activator of the psoriasis-associated proinflammatory cytokine IL-36γ. Proceedings of the National Academy of Sciences, 114 (13). E2748-E2757. ISSN 0027-8424
Abstract
The pro-inflammatory cytokine IL-36γ is highly expressed in epithelial cells and is a pivotal mediator of epithelial inflammation. In particular, IL-36γ is strongly associated with the inflammatory skin disease psoriasis. As with other IL-1 cytokines, IL-36γ is expressed as an inactive precursor and must be processed by specific proteases to become bioactive. Our aim therefore was to identify protease/s capable of IL-36γ activation and explore the importance of this activation in psoriasis. Using a keratinocyte-based activity assay in conjunction with small-molecule inhibitors and siRNA gene silencing, cathepsin S was identified as the major IL-36γ-activating protease expressed by epithelial cells. Interestingly, cathepsin S activity was strongly upregulated in samples extracted from psoriasis patients, relative to healthy controls. In addition, IL-36γ-Ser18, identified as the main product of cathepsin S-dependent IL-36γ cleavage, induced psoriasiform changes in human skin-equivalent models. Together, these data provide important mechanistic insights into the activation of IL-36γ, and highlight that cathepsin S-mediated activation of IL-36γ may be important in the development of numerous IL-36γ driven pathologies, in addition to psoriasis.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | This is an author produced version of a paper published in Proceedings of the National Academy of Sciences. Uploaded in accordance with the publisher's self-archiving policy. In order to comply with the publisher requirements the University does not require the author to sign a non-exclusive licence for this paper. |
Keywords: | psoriasis; inflammation; IL-1; cytokine; IL-36 |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) > Molecular Virology (Leeds) The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Institute of Rheumatology & Musculoskeletal Medicine (LIRMM) (Leeds) > Experimental Musculoskeletal Medicine (Leeds) |
Funding Information: | Funder Grant number Leeds Foundation For Dermatological Research Not Known |
Depositing User: | Symplectic Publications |
Date Deposited: | 23 Feb 2017 14:37 |
Last Modified: | 10 Sep 2020 07:51 |
Published Version: | https://doi.org/10.1073/pnas.1620954114 |
Status: | Published |
Publisher: | National Academy of Sciences |
Identification Number: | 10.1073/pnas.1620954114 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:112691 |