Conflicting vascular and metabolic impact of the IL-33/sST2 axis

Abstract

Interleukin 33 (IL-33), which is expressed by several immune cell types, endothelial and epithelial cells, and fibroblasts, is a cytokine of the IL-1 family that acts both intra- and extracellularly to either enhance or resolve the inflammatory response. Intracellular IL-33 acts in the nucleus as a regulator of transcription. Once released from cells by mechanical stress, inflammatory cytokines, or necrosis, extracellular IL-33 is proteolytically processed to act in an autocrine/paracrine manner as an 'alarmin' on neighbouring or various immune cells expressing the ST2 receptor. Thus, IL-33 may serve an important role in tissue preservation and repair in response to injury; however, the actions of IL-33 are dampened by a soluble form of ST2 (sST2) that acts as a decoy receptor and is produced by endothelial and certain immune cells. Accumulating evidence supports the conclusion that sST2 is a biomarker of vascular health with diagnostic and/or prognostic value in various cardiovascular diseases, including coronary artery disease, myocardial infarction, atherosclerosis, giant-cell arteritis, acute aortic dissection, and ischaemic stroke, as well as obesity and diabetes. Although sST2 levels are positively associated with cardiovascular disease severity, the assumption that IL-33 is always beneficial is naïve. It is increasingly appreciated that the pathophysiological importance of IL-33 is highly dependent on cellular and temporal expression. Although IL-33 is atheroprotective and may prevent obesity and type 2 diabetes by regulating lipid metabolism, IL-33 appears to drive endothelial inflammation. Here, we review the current knowledge of the IL-33/ST2/sST2 signalling network and discuss its pathophysiological and translational implications in cardiovascular diseases.

Gestational diabetes impacts fetal precursor cell responses with potential consequences for offspring

“…Less consistent is the behavior of IL‐33, an interleukin involved in the maintenance of tissue homeostasis, resolution of inflammation, and repair of tissue damage . IL‐33 is considered to have pro‐ and anti‐inflammatory actions and it is released after cell injury, acting as an alarm signal that alerts immune cells about tissue damage . Our results showed a decreased IL‐33 expression in GDM‐derived AMSCs whereas in vitro control AMSCs exposed to a GDM‐like milieu showed an upward trend.…”

Cardioprotective cytokine interleukin‐33 is up‐regulated by statins in human cardiac tissue

“…47,48 We showed previously the intracellular expression of IL-33 in human cardiac myocytes and fibroblasts, and the release of IL-33 during necrosis of these cells. 27 Moreover, the "decoy" receptor for IL-33, sST2, was shown to have predictive value in patients with coronary artery disease and HF 16,[49][50][51] as well as in critically ill patients. 52 In our study presented here, we found that fluvastatin is able to reduce secretion of sST2 from human cardiac myocytes.…”

“…As an inflammatory mediator IL-33 plays a role in a variety of diseases such as bronchial asthma, inflammatory bowel diseases, and rheumatoid arthritis. 16 On the other hand, IL-33 antagonised prohypertrophic stimuli in rat neonatal cardiomyocytes and exhibited an anti-hypertrophic effect after transverse aortic constriction (TAC) in mice. 21 Furthermore, IL-33 protected rat neonatal cardiomyocytes from hypoxia-induced apoptosis and improved cardiac function in rats after experimental myocardial infarction.…”

“…IL‐33 belongs to the IL‐1 family of cytokines . Depending on the experimental model and the pathophysiological context IL‐33 can act either pro‐ or anti‐inflammatory . In the heart, IL‐33 is believed to be cardioprotective as it was shown to possess anti‐hypertrophic and anti‐apoptotic properties in animal models of pressure overload or myocardial infarction, respectively …”

“…can act either pro-or anti-inflammatory. 3,[16][17][18][19][20] In the heart, IL-33 is believed to be cardioprotective as it was shown to possess antihypertrophic and anti-apoptotic properties in animal models of pressure overload or myocardial infarction, respectively. [21][22][23][24] In this study, we aimed to explore if statins and BPs can influence the expression of IL-33 in human adult cardiac myocytes and fibroblasts, and to reveal the responsible mechanisms.…”