Reduced concentrations of the B cell cytokine interleukin 38 are associated with cardiovascular disease risk in overweight subjects
Dennis M. de Graaf, Martin Jaeger, Inge van den Munckhof, Rob ter Horst, Kiki Schraa, Jelle Zwaag, Matthijs Kox, Mayumi Fujita, Takeshi Yamauchi, Laura Mercurio, Stefania Madonna, Joost H.W. Rutten, Jacqueline de Graaf, Niels P. Riksen, Frank L. van de Veerdonk, Mihai G. Netea, Leo A. B. Joosten, Charles A. Dinarello
Abstract
Abstract The IL‐1 family member IL‐38 (IL1F10) suppresses inflammatory and autoimmune conditions. Here, we report that plasma concentrations of IL‐38 in 288 healthy Europeans correlate positively with circulating memory B cells and plasmablasts. IL‐38 correlated negatively with age ( p = 0.02) and was stable in 48 subjects for 1 year. In comparison with primary keratinocytes, IL1F10 expression in CD19 + B cells from PBMC was lower, whereas cell‐associated IL‐38 expression was comparable. In vitro, IL‐38 is released from CD19 + B cells after stimulation with rituximab. Intravenous LPS in humans failed to induce circulating IL‐38, compared to 100‐fold induction of IL‐6 and IL‐1 receptor antagonist. In a cohort of 296 subjects with body mass index > 27 at high risk for cardiovascular disease, IL‐38 plasma concentrations were significantly lower than in healthy subjects ( p < 0.0001), and lowest in those with metabolic syndrome ( p < 0.05). IL‐38 also correlated inversely with high sensitivity C‐reactive protein ( p < 0.01), IL‐6, IL‐1Ra, and leptin ( p < 0.05). We conclude that a relative deficiency of the B cell product IL‐38 is associated with increased systemic inflammation in aging, cardiovascular and metabolic disease, and is consistent with IL‐38 as an anti‐inflammatory cytokine.