Interleukin-33 and soluble suppression of tumorigenicity 2 in scleroderma cardiac involvement

Abstract

Interleukin (IL)-33 is part of the IL-1 family of cytokines and soluble suppression of tumorigenicity 2 (sST2) is part of the family of IL-1 receptors. In systemic sclerosis (SSc), IL-33 and sST2 are involved in cardiac manifestations such as diastolic dysfunction (DD), autonomic dysfunction (AD) and right ventricular–pulmonary arterial coupling assessed by tricuspid annular plane systolic excursion (TAPSE)/systolic pulmonary artery pressure (sPAP). Serum levels of IL33 and sST2 were assessed in 50 SSc patients and 14 healthy controls (HC). Clinical assessment, echocardiography and heart rate variability (HRV) analysis were performed in SSc patients. Serum levels of IL-33 and sST2 were significantly higher in SSc patients than HC. A linear positive correlation between modified Rodnan skin score and IL33 was observed. Serum values of sST2 were higher in SSc patients with DD than in patients without DD [15403 pg/ml (12,208–19,941) vs 8556 pg/ml (6820–11,036), p < 0.001]. sST2 showed a negative correlation with standard deviation of normal-to-normal RR intervals (SDNN) (r = − 0.281, p < 0.05) and positive correlation with low frequency/high frequency (LF/HF) (r = 0,349, p < 0.01). Negative linear correlation exists between sST2 and TAPSE/sPAP (r = − 0.398, p < 0.01). Serum levels of IL-33 and sST2 are higher in SSc patients than HC. Serum levels of sST2 are a potential marker of DD, AD and right ventricular–pulmonary arterial coupling.

Roles of IL-33 in the Pathogenesis of Cardiac Disorders

“…72 In systemic sclerosis, an increase in IL-33 and sST2 are associated with the involvement of the heart such as cardiac diastolic dysfunction, and the sST2 exhibited a negative linear correlation with diastolic dysfunction. 73 Another study also revealed increased IL33 and sST2 in systemic sclerosis patients that are associated with microvascular damage. 74 It was reported that serum sST2 and IL-33 were dramatically higher in atrial fibrillation patients than in healthy volunteers.…”

Current Trends in Vascular Biomarkers for Systemic Sclerosis: A Narrative Review

“…Circulating IL18 levels were found to be significantly higher in SSc patients respect to controls [ 134 , 135 ] and, interestingly, serum levels of IL18-binding protein isoform a (IL18BPa), a soluble decoy receptor for IL18, were also found to be elevated in SSc circulation and to positively correlate with sPAP [ 136 ]. As far as IL33 is concerned, different studies reported a significant increase in its circulating levels in SSc [ 137 , 138 , 139 , 140 , 141 ], particularly in patients with DUs [ 137 , 141 ]. Notably, circulating values of soluble suppression of tumorigenicity 2 (ST2), a member of the IL1R/Toll-like receptor family that IL33 binds to, were also found to be higher in SSc patients and to correlate with diastolic dysfunction, sPAP, DUs, and NVC abnormalities [ 140 , 141 ].…”

“…As far as IL33 is concerned, different studies reported a significant increase in its circulating levels in SSc [ 137 , 138 , 139 , 140 , 141 ], particularly in patients with DUs [ 137 , 141 ]. Notably, circulating values of soluble suppression of tumorigenicity 2 (ST2), a member of the IL1R/Toll-like receptor family that IL33 binds to, were also found to be higher in SSc patients and to correlate with diastolic dysfunction, sPAP, DUs, and NVC abnormalities [ 140 , 141 ]. In particular, ST2 was increased in SSc patients with diastolic dysfunction and lower in those with elevated sPAP [ 140 ].…”

“…Notably, circulating values of soluble suppression of tumorigenicity 2 (ST2), a member of the IL1R/Toll-like receptor family that IL33 binds to, were also found to be higher in SSc patients and to correlate with diastolic dysfunction, sPAP, DUs, and NVC abnormalities [ 140 , 141 ]. In particular, ST2 was increased in SSc patients with diastolic dysfunction and lower in those with elevated sPAP [ 140 ]. Moreover, SSc patients showing DUs and a late NVC pattern had higher ST2 levels than those without DUs and presenting an active NVC pattern [ 141 ], with ST2 being associated with the development of new DUs [ 141 ].…”

The Beta secretase BACE1 drives fibroblasts activation in Systemic Sclerosis through the APP/β-catenin/Notch signalling axis

“…BACE1 can also target the IL-1 receptor 2 (IL-1R2) for cleavage, modulating systemic IL-1 activity through soluble IL1R2 release (12). This is interesting as several IL-1 family members including IL-33 have been implicated in SSc (13). Furthermore, BACE1 expression levels are upregulated by NF-κB through binding of the p65 subunit to the BACE1 promoter (14).…”