Interleukin 38 Protects Against Lethal Sepsis

Background. Interleukin 38 (IL-38) is the most recently characterized cytokine of the interleukin 1 family. However, its role in sepsis remains unknown. Methods. Circulating IL-38 levels were measured in 2 cohorts of adult and pediatric patients with sepsis. Using 2 murine models of lipopolysaccharide (LPS)-induced endotoxemia and cecal ligation and puncture (CLP)-induced sepsis, the effects of IL-38 on survival, inflammation, tissue injury, and bacterial clearance were assessed. Results. Serum IL-38 concentrations were significantly elevated in adult and pediatric patients with sepsis relative to corresponding healthy adult and pediatric controls, respectively. An increased IL-38 level negatively correlated with the number of blood leukocytes and with the level of inflammatory cytokines, including interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) in clinical sepsis. Anti-IL-38 antibody impaired survival and while recombinant IL-38 improved survival in the 2 murine models of LPS-induced endotoxemia and CLP-induced sepsis. IL-38 administration decreased the inflammatory response, as reflected by lower levels of cytokines and chemokines (including IL-6, TNF-alpha, interleukin 10, interleukin 17, interleukin 27, CXCL1, and CCL2), and less damage to tissues (including lung, liver, and kidney) in CLP-induced sepsis. Furthermore, IL-38 augmented bacterial clearance in CLP-induced polymicrobial sepsis. Conclusions. These findings suggest that IL-38 attenuates sepsis by decreasing inflammation and increasing bacterial clearance, thus providing a novel tool for antisepsis therapy.