IL-37 is a fundamental inhibitor of innate immunity

Abstract

The function of interleukin 37 (formerly IL-1 family member 7) remains elusive. Expression of IL-37 in macrophages or epithelial cells imparted near complete suppression of pro-inflammatory cytokines, whereas the abundance of these cytokines increased with silencing of endogenous IL-37 in human blood cells. Anti-inflammatory cytokines remained unchanged under similar conditions. IL-37-transgenic mice were protected from lipopolysaccharide-induced shock, exhibiting markedly improved lung and kidney function and reduced liver damage. IL-37-transgenic mice had less circulating and tissue cytokines (72-95% lower) than wild-type mice and exhibited less dendritic cell activation. IL-37 interacted intracellularly with Smad3 and IL-37-expressing cells and transgenic mice exhibited less cytokine suppression when endogenous Smad3 was depleted. IL-37 thus emerges as a natural suppressor of innate inflammatory and immune responses.

Biochemical Regulation of Sleep and Sleep Biomarkers

“…Some endogenous molecules inhibit IL1 and TNF and also attenuate spontaneous NREMS including IL-4, IL-10, IL-13, 3 corticotrophin releasing hormone, 35 IL1-receptor antagonist, 4 and others (see Figure 1). We have recently found that transgenic mice with the ability to express human IL-37b, a suppressor of multiple pro-somnogenic cytokines 36 sleep less after sleep deprivation than under baseline conditions. 37 Finally, IL1 and TNF vary with sleep propensity.…”

Prognostic significance of nomograms integrating IL‐37 expression, neutrophil level, and MMR status in patients with colorectal cancer

“…Interleukin (IL)‐37 is a new member of the IL‐1 family that encompasses 11 structurally related members sharing a β‐barrel motif 7. Nevertheless, entirely distinct with most IL‐1 family members, that are characterized with proinflammatory functions, IL‐37 has emerged as an important inhibitor of the innate immune response.…”

Interleukin-37: A Peacekeeper at the Intestinal Borders

“…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].…”

“…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].…”

“…Alternatively, (and similar to IL-1a and IL-33), IL-37 may serve as an intracellular nuclear factor, directly binding to DNA elements and downregulating transcription of proinflammatory mediators. In order for nuclear translocation to occur, IL-37 requires the presence of phosphorylated-SMAD3 protein [2]. Importantly, IBD patients usually have elevated gut mucosal levels of SMAD7 at initial evaluation [13], which block the anti-inflammatory activities of transforming growth factor (TGF)b through potent inhibition of SMAD3 phosphorylation [14].…”