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Interleukin-36: Structure, Signaling and Function

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Protein Reviews

Part of the book series: Advances in Experimental Medicine and Biology ((PROTRE,volume 21))

Abstract

The IL-36 family belongs to a larger IL-1 superfamily and consists of three agonists (IL-36α/β/γ), one antagonist (IL-36Ra), one cognate receptor (IL-36R) and one accessory protein (IL-1RAcP). The receptor activation follows a two-step mechanism in that the agonist first binds to IL-36R and the resulting binary complex recruits IL-1RAcP. Assembled ternary complex brings together intracellular TIR domains of receptors which activate downstream NF-κB and MAPK signaling. Antagonist IL-36Ra inhibits the signaling by binding to IL-36R and preventing recruitment of IL-1RAcP. Members of IL-36 are normally expressed at low levels. Upon stimulation, they are inducted and act on a variety of cells including epithelial and immune cells. Protease mediated N-terminal processing is needed for cytokine activation. In the skin, the functional role of IL-36 is to contribute to host defense through inflammatory response. However, when dysregulated, IL-36 stimulates keratinocyte and immune cells to enhance the Th17/Th23 axis and induces psoriatic-like skin disorder. Genetic mutations of the antagonist IL-36Ra are associated with occurrence of generalized pustular psoriasis, a rare but life-threatening skin disease. Anti-IL-36 antibodies attenuate IMQ or IL-23 induced skin inflammation in mice, illustrating IL-36’s involvement in mouse model of psoriasis. Other organs such as the lungs, the intestine, the joints and the brain also express IL-36 family members upon stimulation. The physiological and pathological roles of IL-36 are less well defined in these organs than in the skin. In this chapter, current progress on IL-36 protein and biology is reviewed with a discussion on investigative tools for this novel target.

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Acknowledgement

The authors thank Dr. W. Blaine Stine, Dr. Ivan R. Correia and Dr. Yao Fan for their feedbacks on the manuscript.

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  1. Authors Li Zhou and Viktor Todorovic have been equally contributed for this chapter.

Authors and Affiliations

  1. AbbVie Bioresearch Center, Worcester, MA, USA

    Li Zhou

  2. AbbVie Inc., North Chicago, IL, USA

    Viktor Todorovic

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  1. Li Zhou
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  2. Viktor Todorovic
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Correspondence to Li Zhou .

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Editors and Affiliations

  1. Baylor College of Medicine, Houston, TX, USA

    M. Zouhair Atassi

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All authors are employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication.

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Zhou, L., Todorovic, V. (2020). Interleukin-36: Structure, Signaling and Function. In: Atassi, M.Z. (eds) Protein Reviews . Advances in Experimental Medicine and Biology(), vol 21. Springer, Cham. https://doi.org/10.1007/5584_2020_488

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