IL-36 in chronic inflammation and cancer. (October 2020)

• Record Type: Journal Article
• Authors: Neurath, Markus F.
• Is Part Of: Cytokine & growth factor reviews. Volume 55(2020)
• Page Start: 70
• Page End: 79
• Publication Date: 2020-10
• Subjects: IL interleukin -- IBD inflammatory bowel disease -- IEC intestinal epithelial cell -- IFN interferon -- IRF interferon regulatory factor -- STAT signal transducer and activator of transcription; Cytokines -- IL-36 -- Immune cells -- Inflammation; Cytokines -- Periodicals; 571.84
• DOI: 10.1016/j.cytogfr.2020.06.006
• Languages: English
• ISSNs: 1359-6101

Abstract

Graphical abstract: Highlights: Interleukin-36 cytokines belong to the IL-1 family of cytokines and two antagonists of IL-36 function have been identified (IL-36 receptor antagonist). Increased levels of IL-36 cytokines are produced by various immune and non-immune cells in numerous inflammatory or neoplastic disorders. Suppression of IL-36R signaling was effective in murine models of inflammatory disorders of the skin, kidney, lung and gut raising the possibility that blockade of IL-36R signaling events might be relevant for clinical therapy. Initial studies in patients with generalized pustular psoriasis (GPP) suggested potential efficacy of anti-IL-36R antibody therapy; further clinical studies in other chronic inflammatory disorders are ongoing. Abstract: IL-36 belongs to the IL-1 family of cytokines and activates target cells by binding to a specific cytokine receptor (IL-36R) followed by activation of intracellular regulators such as MAP kinases and NF-kappaB. Three subforms of IL-36, denoted IL-36alpha, IL-36beta and IL-36gamma, have been described that require N-terminal cleavage for activation. Functional studies have shown that IL-36 may activate a broad spectrum of immune and non-immune cells such as macrophages, T cells, keratinocytes and epithelial cells in an IL-1-independent fashion and thereby controls various inflammatory or oncogenic processes in the skin, the lung, the kidney, the liver and the intestine, respectively. Based on the presence of mutations of the IL-36RN in patients with generalized pustular psoriasis, successful clinical pilot trials with IL-36R blocking antibodies were conducted in these patients and further studies in patients with autoimmune or chronic inflammatory disorders such as inflammatory bowel diseases are under way. Collectively, these findings highlight a crucial regulatory role of IL-36 signaling in driving various inflammatory disorders that provide a rational basis for clinical targeting of this cytokine.