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

Cardiovasc Res. 2018 Oct 1;114(12):1578-1594. doi: 10.1093/cvr/cvy166.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Cardiovascular Diseases / metabolism*
  • Cardiovascular Diseases / pathology
  • Cell Communication*
  • Diabetes Mellitus, Type 2 / metabolism
  • Endothelial Cells / metabolism*
  • Endothelial Cells / pathology
  • Humans
  • Immune System / metabolism*
  • Immune System / pathology
  • Inflammation / metabolism*
  • Inflammation / pathology
  • Inflammation Mediators / metabolism*
  • Interleukin-1 Receptor-Like 1 Protein / metabolism*
  • Interleukin-33 / metabolism*
  • Lipid Metabolism*
  • Obesity / metabolism
  • Signal Transduction*


  • Biomarkers
  • Inflammation Mediators
  • Interleukin-1 Receptor-Like 1 Protein
  • Interleukin-33