title: Cathepsin S is the major activator of the psoriasis-associated proinflammatory cytokine IL-36γ.
abstract: The proinflammatory 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 up-regulated 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.
authors.affiliation: School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom.
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Ainscough
authors.affiliation: School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom.
authors.forename: Tom
authors.initials: T
authors.lastname: Macleod
authors.affiliation: Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), University of Leeds, Leeds LS7 4SA, United Kingdom.|National Institute for Health Research (NIHR) Leeds Musculoskeletal Biomedical Research Unit (LMBRU), Leeds Teaching Hospitals National Health Service (NHS) Trust, University of Leeds, Leeds LS7 4SA, United Kingdom.
authors.forename: Dennis
authors.initials: D
authors.lastname: McGonagle
authors.affiliation: School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom.
authors.forename: Rosella
authors.initials: R
authors.lastname: Brakefield
authors.affiliation: Department of Dermatology and Allergology, Aachen Faculty of Medicine, Aachen University, Aachen 52074, Germany.
authors.forename: Jens M
authors.initials: JM
authors.lastname: Baron
authors.affiliation: Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), University of Leeds, Leeds LS7 4SA, United Kingdom.
authors.forename: Ade
authors.initials: A
authors.lastname: Alase
authors.affiliation: Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), University of Leeds, Leeds LS7 4SA, United Kingdom; M.Stacey@leeds.ac.uk M.Wittmann@leeds.ac.uk.|National Institute for Health Research (NIHR) Leeds Musculoskeletal Biomedical Research Unit (LMBRU), Leeds Teaching Hospitals National Health Service (NHS) Trust, University of Leeds, Leeds LS7 4SA, United Kingdom.
authors.forename: Miriam
authors.initials: M
authors.lastname: Wittmann
authors.affiliation: School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom; M.Stacey@leeds.ac.uk M.Wittmann@leeds.ac.uk.
authors.forename: Martin
authors.initials: M
authors.lastname: Stacey
mesh_terms: D020816:Amino Acid Motifs; D002403:Cathepsins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004847:Epithelial Cells / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007375:Interleukin-1 / Q000235:genetics* / Q000378:metabolism; D011565:Psoriasis / Q000201:enzymology / Q000235:genetics* / Q000276:immunology
chemical_list: C508589:IL36G protein, human; D018836:Inflammation Mediators; D007375:Interleukin-1; D002403:Cathepsins; C028217:cathepsin S
keywords: IL-1; IL-36; cytokine; inflammation; psoriasis