Interleukin-37: A Peacekeeper at the Intestinal Borders

Digestive Diseases and Sciences, Mar 2017

Luca Pastorelli, Theresa T. Pizarro

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Interleukin-37: A Peacekeeper at the Intestinal Borders

Interleukin-37: A Peacekeeper at the Intestinal Borders Luca Pastorelli 0 1 2 Theresa T. Pizarro 0 1 2 0 Gastroenterology and Digestive Endoscopy Unit, IRCCS Policlinico San Donato , 20097 San Donato Milanese , Italy 1 Department of Biomedical Sciences for Health, University of Milan , 20133 Milan , Italy 2 Department of Pathology, Case Western Reserve University School of Medicine , Cleveland, OH 44106 , USA Luca Pastorelli Discovery and Characterization of IL-37 - The interleukin (IL)-1 family of cytokines encompasses a wide spectrum of soluble mediators and receptor antagonists. Their expression, present in nearly all organ systems, is of particular importance at mucosal barriers interfacing the external microenvironment, such as the skin, the respiratory tract, and the gastrointestinal (GI) system. IL-1 and IL-1-related cytokines are key factors in the promotion, enhancement, and regulation of host innate immunity and in the orchestration of their interplay with the adaptive immune system. Interestingly, several IL-1 family members, including IL-1a/IL-1b, IL-18, and IL-33, display dichotomous, opposing functions in the pathogenesis of chronic intestinal inflammation, by both inducing inflammation and promoting epithelial restitution/repair and mucosal healing [1]. Emerging evidence, however, suggests that the IL-1 family member 7 (IL-1F7), also termed IL-37, possesses predominant and seemingly exclusive anti-inflammatory activities, particularly in the setting of inflammatory bowel disease (IBD) and other colitic conditions. Although the existence of IL-1F7 was discovered in 2000 by in silico studies, the mediator only began to be characterized in terms of its structure, function, and biology a decade later and was subsequently named IL-37 [2]. Seminal studies clearly reported that IL-37 dampens both innate and adaptive immune responses, thus reducing general inflammation; indeed, IL-37, when present during Toll-like/IL-1 receptor stimulation or uric acid sensing, greatly reduces the synthesis of many proinflammatory cytokines [2, 3]. Consistent with these findings, experiments utilizing several different animal models support the concept that IL-37 is protective toward inflammatory conditions, such as endotoxic shock, myocardial infarction, metabolic syndrome, asthma, acute lung injury, and ischemic liver disease [3]. With regard to chronic inflammatory conditions of the GI tract, IL-37 reduces the severity of dextran sulfate sodium (DSS)-induced colitis in mice through decreased colonic production of IL-1b and tumor necrosis factor (TNF), increased IL-10 secretion, and an overall reduction in the number of CD4?IFNc? T lymphocytes [4, 5]. Interestingly, experiments using this model of acute colitis indicate that, from a functional point of view, the most important cellular sources of IL-37 are of hematopoietic and mesenchymal origin [4]. Of note, however, is that mice appear to lack the IL-37 gene [3]. As such, experiments utilizing mouse models of disease, including experimental colitides, have been conducted using IL-37 transgenic mice, genetically engineered to express human IL-37 [4], or normal rodents injected with mesenchymal stromal cells transfected with the human IL-37 gene [5]. Indeed, while these studies provide important insight into IL-37 function, these results should be interpreted with caution, bearing in mind that alternative cellular sources of IL-37 may also contribute substantially to its immunoregulatory activities in the GI tract. Concepts and Controversies Surrounding the Function of IL-37 During Chronic Intestinal Inflammation The study from Gunaltay et al. [6], published in the current issue of Digestive Diseases and Sciences, explores the possibility that colonic epithelial-derived IL-37 promotes the maintenance of intestinal immune homeostasis through the downregulation of gut proinflammatory molecules. Using CRISPR/Cas9 technology in a human colonic epithelial cell line, the authors demonstrate that even a modest reduction in IL-37 expression augments production of chemokines following activation of the Toll-like receptor (TLR)5 signaling pathway after exposure to bacterial-derived flagellin. These findings are notable since they once again emphasize the central importance of the intestinal epithelium in contributing to the regulation of both innate and adaptive immune responses triggered by the gut microbiome [7]. Indeed, the intestinal epithelium is constantly barraged by components of commensal and pathogenic bacteria, as well as by other potentially harmful insults. Depending on the immunological status and genetic predisposition of the host, intestinal epithelial cells respond by producing several proinflammatory molecules, including not only IL-1a, IL-18, and IL-8, and other chemotactic factors [7], but also anti-inflammatory molecules (e.g., IL1Ra, IL-11) that counterbalance innate mucosal immune activation, as it appears to be the case for IL-37. An additiona (...truncated)


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Luca Pastorelli, Theresa T. Pizarro. Interleukin-37: A Peacekeeper at the Intestinal Borders, Digestive Diseases and Sciences, 2017, pp. 1103-1106, Volume 62, Issue 5, DOI: 10.1007/s10620-017-4523-0