714 IL-6 and Soluble IL-6 Receptor – Two Sides of the Same Coin

Abstract

Abstract Introduction Interleukin (IL)-6 is a multifunctional cytokine that has both a pro- and anti-inflammatory role. In many studies, IL-6 has been shown to increase rapidly after burn injury and is associated with poor outcomes. IL-6 can signal via its soluble IL-6 Receptor (sIL-6R) and is referred to as trans-signaling, which is regarded as the pro-inflammatory pathway. The role of sIL-6R post-burn injury has not yet been explored. We hypothesized that patients with a lower ratio of IL-6 to sIL-6R would have worse outcomes. Methods Patients admitted to our burn centre within 7 days of injury were included in this study. Patients were divided into two groups based on IL-6 and sIL-6R levels measured within the first 30 days post-burn injury. Patients were in the high ratio group if their IL-6:sIL-6R ratio was ≥ 0.185. Clinical outcomes included organ biomarkers, morbidities, and hospital length of stay. Groups were compared using Student’s t-test, Mann-Whitney U, and Fisher’s exact test as appropriate; a P value of < 0.05 was considered statistically significant. Results We studied 104 patients, mean age 51 ± 18 years and 24 ± 17% total body surface area (TBSA) burn. There were 49 patients categorized with a low IL-6:sIL-6R ratio and 55 patients with a high IL-6:sIL-6R ratio. Patients in the high IL-6:sIL-6R ratio group had a significantly greater TBSA burn and a significantly greater proportion of patients with inhalation injury (p< 0.05). Levels of sIL-6R were not significantly different among the low and high group (770 ± 264 pg/mL vs. 798 ± 268 pg/mL respectively; p=0.601). However, levels of IL-6 were significantly higher in patients with a high IL-6:sIL-6R ratio (37 IQR 19–97 pg/mL vs. 567 IQR 273–916 pg/mL; p< 0.0001). Mortality was significantly greater in the high IL-6:sIL-6R ratio group (2% vs. 27%; p< 0.001). Conclusions Interestingly, patients with a higher ratio of IL-6:sIL-6R had significantly greater mortality. Using sIL-6R as a marker for the proinflammatory immune response, we expected patients with a lower IL-6:sIL-6R ratio to have poor outcomes which are typically associated with a hyperinflammatory or exaggerated immune response. However, the absolute value of sIL-6R did not differ. This suggests that classic signaling of IL-6 via its membrane bound receptor, with an anti-inflammatory function, is an important factor. Applicability of Research to Practice The opposing pro- and anti-inflammatory function of IL-6 through trans- and classic signaling is contingent on the ratios expressed. The demonstrated increase in classic signaling highlights the importance of measuring both IL-6 and sIL-6R in future studies. Additionally, it lays the foundation for potential precision medicine approaches to selectively block specific signaling pathways.