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.T he interleukin (IL)-1 family cytokines are fundamental regulators of the innate immune system and orchestrate multiple inflammatory responses (1, 2). IL-1 cytokines are produced rapidly following infection or injury and are capable of potently inducing a range of beneficial proinflammatory processes, including additional cytokine expression, antigen-presenting cell migration, and leukocyte activation and infiltration (3-5). The aberrant expression and regulation of IL-1 cytokines is associated with a broad range of immuopathologies, ranging from autoinflammatory to autoimmune disorders (6-8). Therefore, a greater insight into the regulation and function of IL-1 cytokines is not only of academic interest but also of significant therapeutic importance.IL-36α, IL-36β, and IL-36γ are agonistic cytokines and the most recently discovered of the IL-1 family (9). Interestingly, there is growing evidence to suggest that these cytokines are important for the development of several inflammatory disorders, including psoriasis (10). In psoriatic lesions, the IL-36 cytokines have been shown to be among the most specific and highly up-regulated mRNAs relative to other inflammatory skin diseases and healthy controls (11-13). Moreover, hypomorphic mutations in the IL-36 receptor antagonist (IL-36Ra) cause the severe and potentially lethal subtype of psoriasis called pustular psoriasis in a number of cohorts (14, 15). Mouse models further support these observations, showing that IL-36 overexpression in keratinocytes results in a transient inflammatory skin condition resembling psoriasis (16). In addition, IL-36 receptor-deficient mice have been found to be resistant to Imiquimod-induced psoriasiform dermatitis (17). Interestingly, recent studies have also demonstrated a role for the IL-36 recept...

Protection against microbial infection by the induction of inflammation is a key function of the IL-1 superfamily, including both classical IL-1 and the new IL-36 cytokine families. is a frequent human fungal pathogen causing mucosal infections. Although the initiators and effectors important in protective host responses to are well described, the key players in driving these responses remain poorly defined. Recent work has identified a central role played by IL-1 in inducing innate Type-17 immune responses to clear infections. Despite this, lack of IL-1 signaling does not result in complete loss of immunity, indicating that there are other factors involved in mediating protection to this fungus. In this study, we identify IL-36 cytokines as a new player in these responses. We show that infection of the oral mucosa induces the production of IL-36. As with IL-1α/β, induction of epithelial IL-36 depends on the hypha-associated peptide toxin Candidalysin. Epithelial IL-36 gene expression requires p38-MAPK/c-Fos, NF-κB, and PI3K signaling and is regulated by the MAPK phosphatase MKP1. Oral candidiasis in IL-36R mice shows increased fungal burdens and reduced IL-23 gene expression, indicating a key role played by IL-36 and IL-23 in innate protective responses to this fungus. Strikingly, we observed no impact on gene expression of IL-17 or IL-17-dependent genes, indicating that this protection occurs via an alternative pathway to IL-1-driven immunity. Thus, IL-1 and IL-36 represent parallel epithelial cell-driven protective pathways in immunity to oral infection.

Background: Interleukin-1 secretion is an important process in inflammation and thus, the intracellular regulation of these cytokines is of interest.Results: Inhibition of the proteasome in dendritic cells inhibits interleukin-1 degradation and leads to an accumulation of polyubiquitinated interleukin-1.Conclusion: Interleukin-1 cytokines are regulated by polyubiquitination and proteasomal degradation.Significance: Polyubiquitination and degradation are important processes in the intracellular regulation of interleukin-1.

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Summary Epithelial tissues represent vital interfaces between organisms and their environment. As they are constantly exposed to harmful pathogens, innocuous commensals, and environmental microbes, it is essential they sense and elicit appropriate responses toward these different types of microbes. Here, we demonstrate that the epithelial cytokine interleukin-36γ (IL-36γ) acts as a global discriminator of pathogenic and harmless microbes via cell damage and proteolytic activation. We show that intracellular pro-IL-36γ is upregulated by both fungal and bacterial epithelial microbes; yet, it is only liberated from cells, and subsequently processed to its mature, potent, proinflammatory form, by pathogen-mediated cell damage and pathogen-derived proteases. This work demonstrates that IL-36γ senses pathogen-induced cell damage and proteolytic activity and is a key initiator of immune responses and pathological inflammation within epithelial tissues. As an apically located epithelial proinflammatory cytokine, we therefore propose that IL-36γ is critical as the initial discriminator of harmless microbes and invasive pathogens within epithelial tissues.