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
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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.
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