期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 114, 期 13, 页码 E2748-E2757出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1620954114
关键词
psoriasis; inflammation; IL-1; cytokine; IL-36
资金
- Medical Research Council (MRC)
- British Skin Foundation
- NIHR Leeds Musculoskeletal Biomedical Research Unit
- MRC [MR/M01942X/1] Funding Source: UKRI
- British Skin Foundation [5035s] Funding Source: researchfish
- Medical Research Council [MR/M01942X/1] Funding Source: researchfish
The proinflammatory cytokine IL-36. is highly expressed in epithelial cells and is a pivotal mediator of epithelial inflammation. In particular, IL-36. is strongly associated with the inflammatory skin disease psoriasis. As with other IL-1 cytokines, IL-36. 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-36. 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-36 gamma-activating protease expressed by epithelial cells. Interestingly, cathepsin S activity was strongly up-regulated in samples extracted from psoriasis patients relative to healthy controls. In addition, IL-36 gamma-Ser18, identified as the main product of cathepsin S-dependent IL-36. cleavage, induced psoriasiform changes in human skin-equivalent models. Together, these data provide important mechanistic insights into the activation of IL-36. and highlight that cathepsin S-mediated activation of IL-36. may be important in the development of numerous IL36 gamma-driven pathologies, in addition to psoriasis.
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