Interleukin-36 (IL-36) Ligands Require Processing for Full Agonist (IL-36α, IL-36β, and IL-36γ) or Antagonist (IL-36Ra) Activity

Towne, Jennifer E.; Renshaw, Blair R.; Douangpanya, Jason; Lipsky, Brian P.; Shen, Min; Gabel, Christopher A.; Sims, John E.

doi:10.1074/jbc.m111.267922

Cited by 300 publications

(335 citation statements)

References 21 publications

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“…This indicated that sufficient IL-17A was still present in these supernatants that stimulated gene expression. As mentioned above, IL-36 cytokines require processing to gain biological activity [34][35][36] . IL-36 can be processed and activated by proteases derived from neutrophils 25,36 .…”

Section: Resultsmentioning

confidence: 99%

“…IL-36 cytokines that are induced in and secreted by NHEKs in response to IL-17A are inactive (Fig. 2), most likely because of lack of N-terminal processing 35 . In agreement with previous findings 25,36 , IL-36 can be activated by proteases that are released by activated neutrophils, including elastase (Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

“…3e and Supplementary Fig. S3a) 25,[34][35][36]53 . Together, these observations suggest that IL-36 and its processing factors are likely to be important in psoriasis.…”

Section: Discussionmentioning

confidence: 99%

“…It was noted that removing N-terminal amino acids increased their signaling capacity 35 . New results describe neutrophil-derived proteases as well as cathespsin S, a lysosomal protease, as IL-36 cytokine processing enzymes 25,34,36 .…”

Section: Discussionmentioning

confidence: 99%

“…Importantly and similar to other IL-1 family cytokines, the different IL-36 proteins need to be processed to become biologically active. This occurs by truncating the N-termini, removing a few amino acids in response to several different proteases [34][35][36] . Thus, in addition to IL-17, IL-36 cytokines are also thought to participate in the inflammatory progression of psoriasis.…”

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confidence: 99%

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301 The psoriasis-associated IL-17A induces and cooperates with IL-36 cytokines to control keratinocyte differentiation and function

Pfaff

Kluwig

Marquardt

et al. 2017

Journal of Investigative Dermatology

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Psoriasis is a T H 17-driven inflammatory disease affecting a significant proportion of the world population. The molecular consequences of IL-17 signaling in the skin are only partially understood. Therefore, we evaluated the IL-17A effects on organotypic 3-dimensional skin models and observed that IL-17A interfered with keratinocyte differentiation. In agreement with this phenotype, IL-17A repressed the expression of many genes encoding structural proteins. Moreover, genes encoding anti-microbial peptides were induced, resulting in a strengthening of the chemical barrier. Finally, we observed enhanced expression of the three IL-36 cytokines IL-36α, β and γ. We found that IL-36γ was secreted from keratinocytes in an inactive form and that neutrophilic proteases, including elastase, were capable of activating this cytokine. Functionally and similar to IL-17A, truncated IL-36 cytokines interfered with keratinocyte differentiation in 3D models. The molecular analysis revealed strong cooperative effects of IL-17A and IL-36 cytokines in regulating target genes, which was dependent on the proteolytic activation of the latter. Together these findings suggest an amplification cycle that can be initiated by IL-17A, involving IL-36 cytokines and immune cell derived proteases and resulting in active IL-36 cytokines which synergize with IL-17A. This amplification cycle might be relevant for a persistent psoriatic phenotype.Psoriasis, a chronic autoimmune disease of the skin, affects approximately 2% of the population. Psoriasis is associated with systemic inflammatory processes including inflammatory arthritis, inflammatory bowel disease, and metabolic syndrome 1,2 . A typical manifestation of the disease is the hyperproliferation of keratinocytes with premature differentiation. This results in incomplete cornification with retention of nuclei in the stratum corneum, referred to as parakeratosis. Functionally this correlates with increased infiltrations of immune cells due to dendritic cells, macrophages, neutrophils and different subpopulations of T cells. These cells modify the cytokine milieu and thus affect the behavior of keratinocytes resulting in altered differentiation [1][2][3]

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…3e and Supplementary Fig. S3a) 25,[34][35][36]53 . Together, these observations suggest that IL-36 and its processing factors are likely to be important in psoriasis.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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301 The psoriasis-associated IL-17A induces and cooperates with IL-36 cytokines to control keratinocyte differentiation and function

Pfaff

Kluwig

Marquardt

et al. 2017

Journal of Investigative Dermatology

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Production of biologically active IL‐36 family cytokines through insertion of N‐terminal caspase cleavage motifs

et al. 2016

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Recent evidence has strongly implicated IL‐36 cytokines as key initiators of inflammation in the skin barrier. IL‐36 cytokines belong to the extended IL‐1 family and, similar to most members of this family, are expressed as inactive precursors that require proteolytic processing for activation. Because the proteases responsible for activation of members of the IL‐36 subfamily have not been reported, we have developed a method for the production of biologically active IL‐36 through introduction of a caspase cleavage motif, DEVD, within the N‐termini of these cytokines. Here, we show that DEVD‐modified IL‐36α, IL‐36β and IL‐36γ cytokines were highly soluble and were readily processed and activated by caspase‐3. Caspase‐3‐processed IL‐36 family cytokines exhibited robust biological activity on a range of responsive cell types, including primary keratinocytes. We also generated specific polyclonal antibodies against all three IL‐36 family members through immunization with purified recombinant IL‐36 cytokines. The modified forms of IL‐36 described herein will be useful for production of large quantities of biologically active IL‐36 for structure and function studies on these important proinflammatory cytokines.

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Identification of small‐molecule elastase inhibitors as antagonists of IL‐36 cytokine activation

et al. 2018

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IL‐1 family cytokines act as apical initiators of inflammation in many settings and can promote the production of a battery of inflammatory cytokines, chemokines and other inflammatory mediators in diverse cell types. IL‐36α, IL‐36β and IL‐36γ, which belong to the extended IL‐1 family, have been implicated as key initiators of skin inflammation in psoriasis. IL‐36γ is highly upregulated in lesional skin from psoriatic individuals, and heritable mutations in the natural IL‐36 receptor antagonist result in a severe form of psoriasis. IL‐36 family cytokines are initially expressed as inactive precursors that require proteolytic processing for activation. The neutrophil granule‐derived protease elastase proteolytically processes and activates IL‐36α and IL‐36γ, increasing their biological activity ~ 500‐fold, and also robustly activates IL‐1α and IL‐33 through limited proteolytic processing. Consequently, inhibitors of elastase activity may have potential as anti‐inflammatory agents through antagonizing the activation of multiple IL‐1 family cytokines. Using in silico screening approaches, we have identified small‐molecule inhibitors of elastase that can antagonize activation of IL‐36γ by the latter protease. The compounds reported herein may have utility as lead compounds for the development of inhibitors of elastase‐mediated activation of IL‐36 and other IL‐1 family cytokines in inflammatory conditions, such as psoriasis.

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Interleukin-36 (IL-36) Ligands Require Processing for Full Agonist (IL-36α, IL-36β, and IL-36γ) or Antagonist (IL-36Ra) Activity

Cited by 300 publications

References 21 publications

301 The psoriasis-associated IL-17A induces and cooperates with IL-36 cytokines to control keratinocyte differentiation and function

301 The psoriasis-associated IL-17A induces and cooperates with IL-36 cytokines to control keratinocyte differentiation and function

Production of biologically active IL‐36 family cytokines through insertion of N‐terminal caspase cleavage motifs

Identification of small‐molecule elastase inhibitors as antagonists of IL‐36 cytokine activation

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