Molecular Determinants of Agonist and Antagonist Signaling through the IL-36 Receptor

Guenther, S.; Sundberg, Eric J.

doi:10.4049/jimmunol.1400538

Cited by 71 publications

(93 citation statements)

References 44 publications

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“…Our data provide a rational basis for the development of therapies specifically targeting these pathways, particularly the IL-36 system in GPP (48, 49). …”

Section: Discussionmentioning

confidence: 90%

IL-1 and IL-36 are dominant cytokines in generalized pustular psoriasis

Johnston

Xing

Wolterink

et al. 2017

Journal of Allergy and Clinical Immunology

288

378

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Background Generalized pustular psoriasis (GPP) is a rare, debilitating, and often life-threatening inflammatory disease characterized by episodic infiltration of neutrophils into the skin, pustule development, and systemic inflammation, which can manifest in the presence or absence of chronic plaque psoriasis (PV). Current treatments are unsatisfactory warranting a better understanding of GPP pathogenesis. Objective To understand better the disease mechanism of GPP to allow improved targeted therapies. Methods We performed a gene expression study on formalin-fixed paraffin-embedded GPP (n=28) and PV (n=12) lesional biopsies and healthy control (n=20) skin. Differential gene expression was analyzed using gene ontology and enrichment analysis. Gene expression was validated with qRT-PCR and immunohistochemistry, and a potential disease mechanism investigated using primary human cell culture. Results Compared with healthy skin, GPP lesions yielded 479 and PV 854 differentially expressed genes respectively, with 184 upregulated in both diseases. We detected significant contributions of IL-17A, TNF, IL-1, IL-36 and interferons in both diseases; although GPP lesions furnished higher IL-1 and IL-36 and lower IL-17A and interferon-γ mRNA expression than PV. We detected prominent IL-36 expression by keratinocytes proximal to neutrophilic pustules and show that both neutrophils and neutrophil proteases activate IL-36. Suggesting another mechanism regulating IL-36 activity, the protease inhibitors serpin A1 and A3, which inhibit elastase and cathepsin G respectively, were upregulated in both diseases and inhibited activation of IL-36. Conclusions Our data indicate sustained activation of IL-1 and IL-36 in GPP, inducing neutrophil chemokine expression, infiltration and pustule formation, suggesting that the IL-1/IL-36 inflammatory axis is a potent driver of disease pathology in GPP.

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“…Our data provide a rational basis for the development of therapies specifically targeting these pathways, particularly the IL-36 system in GPP (48, 49). …”

Section: Discussionmentioning

confidence: 90%

IL-1 and IL-36 are dominant cytokines in generalized pustular psoriasis

Johnston

Xing

Wolterink

et al. 2017

Journal of Allergy and Clinical Immunology

288

378

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“…Modeling showed that the b4/5 and b11/12 loops in IL-36 likely interact directly with IL-1RAcP. The largest conformational differences between IL-36Ra and IL-36 are found in these two loops and likely explain how IL-36 agonists mediate recruitment of IL-1RAcP, while IL-36Ra does not [89].…”

Section: Il-36ramentioning

confidence: 95%

The interleukin (IL)-1 cytokine family – Balance between agonists and antagonists in inflammatory diseases

et al. 2015

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“…IL-1Ra and IL-36Ra act as competitive antagonists of IL-1 and IL-36, respectively, by binding to the receptors (Fig. 2B) in a manner that does not allow the recruitment of IL-1RAP (20,(38)(39)(40)(41)(42). Because two intracellular domains-one from the receptor and one from the receptoraccessory protein-are required for MyD88 docking ( Fig.…”

Section: Introduction To the Interleukin-1 Familymentioning

confidence: 99%

Interleukin-36 cytokines may overcome microbial immune evasion strategies that inhibit interleukin-1 family signaling

Jensen

2017

Sci. Signal.

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Pathogens deploy immune evasion strategies to successfully establish infections within their hosts. Naturally, the host responds by acquiring mechanisms to counter these strategies. There is increasing evidence that the three interleukin-36 (IL-36) cytokines, IL-36a, IL-36b and IL-36g, play important roles in host immunity. With a focus on the skin as a target for microbial and viral invasion, the current knowledge of IL-36 functions is reviewed. Furthermore, the hypothesis that the IL-36s have evolved to counteract virulence factors is presented using viruses as an example. The IL-36s are related to IL-1a, IL-1b, IL-18, and IL-33. Numerous viruses affecting the skin have developed immune evasion strategies that neutralize IL-1a, IL-1b, or IL-18 signaling or combinations of these pathways. Through small differences in activation mechanisms and receptor utilization, it is possible that IL-36 signaling may proceed unhindered in the presence of these viral inhibitors. Thus, one physiological function of the IL-36s may be to counteract microbial immune evasion.

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Molecular Determinants of Agonist and Antagonist Signaling through the IL-36 Receptor

Cited by 71 publications

References 44 publications

IL-1 and IL-36 are dominant cytokines in generalized pustular psoriasis

IL-1 and IL-36 are dominant cytokines in generalized pustular psoriasis

The interleukin (IL)-1 cytokine family – Balance between agonists and antagonists in inflammatory diseases

Interleukin-36 cytokines may overcome microbial immune evasion strategies that inhibit interleukin-1 family signaling

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