Enhanced IL-6 trans-signaling in pulmonary arterial hypertension and its potential role in disease-related systemic damage

• IL-6 trans-signaling is enhanced in patients with pulmonary arterial hypertension (PAH).
• IL-6 shows prognostic value regarding clinical deterioration in short-term observation.
• sIL-6R might act as a mediator of unfavorable systemic effects of IL-6 signaling in PAH.

BackgroundThe role of IL-6 in pulmonary arterial hypertension (PAH) has been reported but the prevalence of soluble receptors for IL-6: sIL-6R and sgp130 and its potential role in PAH have not been studied. Our aim was to examine the IL-6 together with the soluble receptors and to assess its relationship with clinical status of PAH patients as well as to assess its potential prognostic significance.MethodsSerum concentrations of IL-6, sIL-6R and sgp130 were quantified by ELISA in 26 patients with PAH and 27 healthy controls and related to functional and biochemical parameters and clinical outcome in PAH group. The PAH patients were followed up for 1 year, noting the end point of clinical deterioration (WHO class change, the need for escalation of therapy) or death.ResultsThe PAH group was characterized by higher median serum IL-6 [2.38 (IQR 1.56–3.75) vs 0.87 (0.63–1.3) pg/ml, p = 0.000003] and sIL-6R concentrations [69.7 (IQR 60.4–84.4 vs 45.7 (34.6–70.3) ng/ml, p = 0.0036] compared to control subjects. Both groups did not differ in sgp130 concentrations. There were significant correlations in PAH group between IL-6 levels and uric acid, parameters of ventilatory efficiency in cardiopulmonary exercise testing: VE/VO2, VE/VCO2, VE/VCO2 slope and peak PetCO2. sIL-6R levels inversely correlated with LDL cholesterol. After 1 year the clinical deterioration occurred in 11 patients, 15 remained stable. Patients in whom the clinical deterioration occurred showed significantly higher baseline concentrations of IL-6 [3.25 (IQR 2.46–5.4) pg/ml vs 1.68 (1.38–2.78) pg/ml, p = 0.004], but not sIL-6R. Median IL-6 ⩾ 2.3 pg/ml (91% sensitivity, 73% specificity) identified subjects with worse clinical course. In the univariate analysis, higher IL-6 level at baseline was associated with increased risk and earlier occurrence of clinical deterioration (HR 1.42, 95%CI 1.08–1.85, p = 0.015).ConclusionsIL-6 trans-signaling is enhanced in PAH. Elevated concentration of sIL-6R suggests its potential unfavorable role in systemic amplification of IL-6 signaling in PAH. Levels of IL-6 are associated with clinical indicators of disease severity as well as indirectly with systemic metabolic alterations. IL-6 shows prognostic value regarding predicting clinical deterioration.