ST2 and the ST2/IL-33 signalling pathway-biochemistry and pathophysiology in animal models and humans

ST2 is an interleukin (IL)-1 receptor family member with transmembrane (ST2L) and soluble (sST2) isoforms. Structurally, the ST2 gene products are very similar in mice and humans. In humans and in mice, alternative promoter activation and splicing produce ST2L and sST2. ST2L represents the longest transcript, whereas sST2 is the truncated, soluble isoform. ST2L is the biological receptor for IL-33, a member of the IL-1 family. IL-33 is the functional ligand of ST2L and signals the presence of tissue damage to local immune cells. IL-33/ST2L signalling leads to the production of inflammatory cytokines/chemokines and to the induction of the immune response. Conversely, sST2 functions as a decoy receptor for IL-33, inhibiting the effects of IL-33/ST2L signalling. Animal studies have allowed the investigation of ST2 and the IL-33/ST2L signalling pathway at multiple levels. However, clinical studies have mainly focused on the determination of sST2 in the circulation. In humans, plasma concentrations of sST2 increase in several diseases, such as heart disease, pulmonary disease, burn injury and graft-versus-host disease. Consequently, increased plasma concentrations of sST2 are not specific for a single disorder in humans and are thus of limited value for diagnostic purposes. However, increased plasma concentrations of sST2 have been linked to a worse prognosis in numerous diseases. Nevertheless, the major source of circulating sST2 in healthy and diseased humans is currently not fully established. In addition, whether the downregulation of sST2 can improve the outcome of patients in the clinical setting has not been elucidated. The aim of the present review was to provide an update on the findings regarding the biochemistry and pathophysiology of ST2 and the sST2 signalling pathway in humans and experimental models.