Elevated sGP130 characterises dysregulated chronic inflammation in diabetic peripheral vascular disease

Abstract Introduction Chronic systemic inflammation is integral to the pathophysiology of cardiovascular disease and diabetes mellitus. Interleukin 6 (IL-6) is a cytokine which may stimulate either pro- or anti-inflammatory activity depending cell population. Classical IL-6 signalling only occurs in cells expressing membrane-bound IL-6 receptor, and results in anti-inflammatory JAK/STAT3 pathway activation. Trans-signalling, by contrast, involves soluble IL-6 receptor α and soluble glycoprotein 130 (sGP130), and therefore may affect any cell regardless of membrane receptor expression. We designed a study to characterise Interleukin-6 (IL-6) trans-signalling in a diabetic cohort receiving treatment for symptomatic peripheral vascular disease and identify whether IL-6 signalling is correlated to outcomes in this patient group. Methods A single-centre, prospective cohort study of patients with DM undergoing infra-inguinal revascularization was conducted. Pre-operative serum was obtained from patients, who were then followed and observed for major amputation, death, and need for re-intervention as primary outcomes. Quantitative serum assays for IL-6, sIL-6rα, and sGP130 were performed. Results 40 patients (20 controls) were included in the study. Diabetic peripheral vascular disease patients had significantly higher serum IL-6 (p=0.0038), as well as higher serum sGP130 (p=0.0119) at baseline. Significant correlation was found between serum IL-6 and C-reactive Protein (p= 0.02), and serum IL-6 and sGP130 (p=0.02) in the disease group, but not in controls. sGP130 was higher in patients who reached primary outcomes (p=0.0196). Conclusion Systemic IL-6 trans-signalling is dysregulated in diabetic peripheral vascular disease and may be a future therapeutic target or adjunct to surgical management. Elevated sGP130 may be a prognostically-relevant biomarker in this population.