Distinct expression of interleukin (IL)-36<b>α, β</b> and <b>γ</b>, their antagonist IL-36Ra and IL-38 in psoriasis, rheumatoid arthritis and Crohn's disease

Boutet, Marie-Astrid; Bart, Géraldine; Penhoat, M.; Amiaud, Jérôme; Brulin, Bénédicte; Charrier, Céline; Morel, Franck; Lecron, Jean‐Claude; Rolli–Derkinderen, Malvyne; Bourreille, Arnaud; Vigne, Solenne; Gabay, Cem; Palmer, Gaby; Goff, Benoît Le; Blanchard, Frédéric

doi:10.1111/cei.12761

Cited by 223 publications

(288 citation statements)

References 47 publications

(87 reference statements)

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“…This is evident in the rare autoinflammatory diseases deficiency of the IL-1Ra (DIRA) and deficiency of the IL-36Ra (DITRA), where patients present with severe pustular skin eruptions (35). As well as its apparent pathological role in inflammation, IL-36γ is also involved in wound repair within epithelial compartments (9,36,37). Thus, a comprehensive understanding of IL-36γ activation in the epithelium is imperative.…”

Section: Discussionmentioning

confidence: 99%

Cathepsin S is the major activator of the psoriasis-associated proinflammatory cytokine IL-36γ

Ainscough

Macleod

McGonagle

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

120

112

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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...

show abstract

Section: Discussionmentioning

confidence: 99%

Cathepsin S is the major activator of the psoriasis-associated proinflammatory cytokine IL-36γ

Ainscough

Macleod

McGonagle

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

120

112

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“…We have previously shown that IL-38 mRNA levels are enhanced in synovial membranes of patients with RA and in colons of patients with Crohn's disease. In contrast, IL-38 expression was decreased in psoriatic skin 3. IL-38 protein levels were also enhanced in the synovial fluid of patients with RA 3…”

Section: Introductionmentioning

confidence: 91%

“…It was shown that apoptotic cells were able to produce a mature, truncated form of IL-38, but the exact cleavage site and the protease responsible for this maturation are not yet identified 2. Recently we have shown that IL-38 is expressed by keratinocytes, synovial fibroblast from patients with rheumatoid arthritis (RA), as well as by human monocytes and type I macrophages (M1) polarised in vitro 3. IL-38 gene polymorphisms are associated with RA, psoriatic arthritis, ankylosing spondylitis and heart disease 4–8.…”

Section: Introductionmentioning

confidence: 99%

IL-38 overexpression induces anti-inflammatory effects in mice arthritis models and in human macrophages in vitro

et al. 2017

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“…IL-36β is constitutively expressed in human articular chondrocytes, and stimulation of both synovial fibroblasts and articular chondrocytes by recombinant IL-36β induces proinflammatory cytokine responses [40]. In mice with CIA and in the synovium of patients with RA, IL-36α, IL-36β, IL-36γ, IL-36Ra and IL-38 were all elevated and correlated with IL-1β, CCL3, CCL4 and macrophage (M)-CSF, but not with Th17 cytokines [41]. Expression of IL-36R and its ligands IL-36α and IL-36Ra has been detected in the synovial lining layer and cellular infiltrates of patients with inflammatory arthritis [42].…”

Section: Il-36 and Il-38mentioning

confidence: 99%

“…Of note, IL-38 overexpression did not induce the production of other anti-inflammatory cytokines, but reduced significantly IL-10 expression. IL-38 levels are increased in the synovial membrane and sera from patients with RA compared with healthy controls [47,49] IL-38 is expressed by keratinocytes, synovial fibroblast from patients with RA, as well as by human monocytes and type I macrophages polarized in vitro [41].…”

Section: Il-36 and Il-38mentioning

confidence: 99%

Cytokines in the pathogenesis of rheumatoid arthritis: new players and therapeutic targets

et al. 2017

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In recent years, the landscape of pro- and anti-inflammatory cytokines has rapidly expanded with the identification of new members proven to be involved at different extent in the pathogenesis of chronic immune mediated inflammatory diseases including rheumatoid arthritis (RA). The advance of our understanding of mediators involved in the pathogenesis of RA and in consequence, the development of novel targeted therapies is necessary to provide patients not responding to currently available strategies with novel compounds. The aim of this review article is to provide an overview on recently identified cytokines, emphasizing their pathogenic role and therapeutic potential in RA. A systematic literature review was performed to retrieve articles related to every cytokine discussed in the review. In some cases, evidence from animal models and RA patients is already consistent to move forward into drug development. In others, conflicting observation and the paucity of data require further investigations.Forty years after the discovery of IL-1, the landscape of cytokines is continuously expanding with increasing possibilities to develop novel therapeutic strategies in RA. Electronic supplementary material The online version of this article (10.1186/s41927-017-0001-8) contains supplementary material, which is available to authorized users.

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Distinct expression of interleukin (IL)-36α, β and γ, their antagonist IL-36Ra and IL-38 in psoriasis, rheumatoid arthritis and Crohn's disease

Cited by 223 publications

References 47 publications

Cathepsin S is the major activator of the psoriasis-associated proinflammatory cytokine IL-36γ

Cathepsin S is the major activator of the psoriasis-associated proinflammatory cytokine IL-36γ

IL-38 overexpression induces anti-inflammatory effects in mice arthritis models and in human macrophages in vitro

Cytokines in the pathogenesis of rheumatoid arthritis: new players and therapeutic targets

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