CLASSIC IL-6 SIGNALING IS ASSOCIATED WITH POOR OUTCOMES IN BURN PATIENTS

ABSTRACT: Background: Interleukin (IL)-6 is a multifunctional cytokine with both a proinflammatory and anti-inflammatory role. In many studies, IL-6 increases rapidly after burn injury and is associated with poor outcomes. However, there are two aspects to IL-6; it can signal via its soluble IL-6 receptor (sIL-6R), which is referred to as trans-signaling and is regarded as the proinflammatory pathway. The role of sIL-6R postburn injury has yet to be explored in its entirety. We hypothesized that patients with a lower ratio of IL-6 to sIL-6R would have worse outcomes. Methods: Patients admitted to our burn center 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 7 days postburn 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 86 patients with a median age of 50 years (36-66 years) and a median total body surface area burn of 18% (10-31). There were 40 patients categorized with a low IL-6/sIL-6R ratio and 46 patients with a high IL-6/sIL-6R ratio. Patients in the high IL-6/sIL-6R ratio group had a significantly greater total body surface area burn ( P < 0.001) and a significantly greater proportion of patients with inhalation injury ( P = 0.001). Levels of IL-6 were significantly higher in patients with a high IL-6/sIL-6R ratio ( P < 0.0001). However, levels of sIL-6R were not significantly different among the low and high groups ( P = 0.965). Mortality was significantly greater in the high IL-6/sIL-6R ratio group (3% vs. 26%; P = 0.002). 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, typically associated with a hyperinflammatory or exaggerated immune response. However, the absolute value of sIL-6R did not differ. This suggests that classical signaling of IL-6 via its membrane-bound receptor, with an anti-inflammatory function, is important.