Abstract
Interleukin (IL)-37 has an important function in limiting excessive inflammation. Its expression is increased in numerous inflammatory and autoimmune conditions and correlates with disease activity, suggesting it could have potential as a disease biomarker. Nevertheless, a reference range has yet to be determined. Our aim was to establish the first reference range of circulating IL-37 levels in healthy adult humans. PubMed was searched for studies reporting blood IL-37 concentrations in healthy adult subjects as measured by enzyme-linked immunosorbent assay. Nineteen studies were included in the analysis. Mean IL-37 levels were weighted by sample sizes, and weighted mean lower and upper levels ( ± 2SD of means) were calculated to provide a weighted mean and reference range. IL-37 levels were quantified in either serum or plasma from a total of 1035 (647 serum; 388 plasma) healthy subjects. The serum, plasma and combined matrix weighted means (reference ranges) were 72.9 (41.5 – 104.4) pg/mL, 83.9 (41.1 – 126.8) pg/mL, and 77.1 (41.4 – 112.8) pg/mL, respectively. There were no significant differences between serum and plasma means and upper and lower limits. Study means and upper IL-37 levels were significantly higher in Chinese population studies. From our analysis, a preliminary reference range for circulating IL-37 levels in healthy human adults has been established. In order to determine a reliable reference range for clinical application, large, prospective, multi-ethnic, healthy population studies are necessary. In addition, demographics, sample matrix, collection, processing and storage methods potentially affecting IL-37 detection levels should be thoroughly investigated.
Highlights
Interleukin (IL)-37, formally known as IL-1 family member 7 (IL-1F7), is the second most recent addition to the IL-1 family [1,2,3]
A Medline search was performed via PubMed for peer-reviewed articles published up to the 1st March 2021 that reported on blood IL-37 concentrations in healthy humans using the following search term: AND AND
Studies were excluded if they met any of the following exclusion criteria: 1) only genetic or gene expression studies; 2) cell/tissue studies; 3) animal model studies; 4) IL-37 levels measured in non-blood matrix; 5) healthy control subjects considered non ‘normal’; 6) healthy subjects < 18 years of age; 7) numerical values of mean (SD) circulating IL-37 not reported/available; 8) only median IL-37 levels reported; 9) extrapolated IL-37 levels reported; 10) large standard deviations that result in calculation of negative lower limit values; 11) quantification by method other than enzyme-linked immunosorbent assays (ELISA); 12) not IL-37
Summary
Interleukin (IL)-37, formally known as IL-1 family member 7 (IL-1F7), is the second most recent addition to the IL-1 family [1,2,3]. Unlike most IL-1 family members, which are pro-inflammatory, IL-37 has anti-inflammatory actions [4]. Research over the last decade has provided detailed insights into the fundamental mechanisms of action of IL-37, and highlighted its key role in Circulating IL-37 Levels in Healthy Humans suppressing innate immune and inflammatory responses [3,4,5,6]. IL-37 is a potent inhibitor of proinflammatory cytokine production, in particular, but not limited to, TNF, IL-1ß and IL-6 [6]. IL-37 likely acts as a negative feedback mechanism to limit excessive inflammation [3, 13]. One mechanism by which IL-37 suppresses pro-inflammatory cytokine production is by “switching off” metabolic activation in monocytes [13]
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